Anthranilic acid derivatives

ABSTRACT

The present invention provides an anthranilic acid derivative having a cGMP-PDE inhibitory activity. 
     An anthranilic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof: ##STR1##  wherein R 1 , R 2 , R 3  and R 4  represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, a nitro group, a hydroxyalkyl group, a cyano group or the like; R 5  and R 6  represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group or the like; 
     W represents a group of the formula: --N═ or --CH═; R 7  and R 8  represent the same or different from each other, a hydrogen atom, an optionally halogenated lower alkyl group or the like; 
     A represents a hydrogen atom, an optionally halogenated lower alkyl group or the like; 
     Y represents an oxygen atom or a sulfur atom; and 
     n is an integer of 0 to 6!.

FIELD OF THE INVENTION

The present invention relates to an anthranilic acid derivative havingan excellent activity as a drug.

BACKGROUND OF THE INVENTION AND PRIOR ART

Angina pectoris which is one of ischemic heart diseases has been knownas a disease which frequently attacks the aged. Although nitrate andnitrite compounds, calcium antagonist, β-blocker and so forth have beenused as remedies therefor, these drugs are still insufficientlyeffective in treating angina pectoris or in preventing the evolutionthereof into myocardial infarction. Further, there have recently beenobserved lowering in the age of patient with angina pectoris andcomplication of condition of the patient owing to the change in lifestyle and the stress increased by the complication of social mechanism,so that the development of a new type of more excellent drug has beeneagerly expected.

With respect to the nitrate and nitrite compounds among theabove-mentioned drugs currently used, it is believed that the actionthereof relates to cyclic GMP (hereinafter abbreviated to "cGMP") whichis one of the cyclic nucleotides known as intracellular secondmessenger. Further, it is well known that cGMP has a relaxant activityon vascular and bronchial smooth muscles. Although the mechanism ofaction of these drug is not always apparent, the above activity of cGMPis generally believed to be due to the synthesis of cGMP accelerated byan activated guanylate cyclase. However, these drugs exhibit lowbioavailability and relatively short action time, and the occurrence oftolerance thereto has been reported, which becomes a clinical problem.

DISCLOSURE OF THE INVENTION

Under these circumstances, the inventors of the present inventionstarted studies to develop a new type of more excellent drug.

Namely, the inventors of the present invention have directed theirattention to an inhibitory activity against cGMP phosphodiesterase(hereinafter abbreviated to "cGMP-PDE") and have intensively studied oncompounds having such an activity for many years. As a result of thestudies, they have found that an anthranilic acid derivative which willbe described below has these activity and is efficacious for variousischemic heart diseases. The present invention has been accomplished onthe basis of this finding.

The present invention relates to an anthranilic acid derivativerepresented by the following general formula (I) or a pharmacologicallyacceptable salt thereof: ##STR2## wherein R¹, R², R³ and R⁴ representthe same or different from each other, a hydrogen atom, a halogen atom,a hydroxy group, an optionally halogenated lower alkyl group, anoptionally halogenated lower alkoxy group, a nitro group, a hydroxyalkylgroup, a cyano group, a group of the formula: ##STR3## (wherein R⁹ andR¹⁰ represent the same or different from each other, a hydrogen atom, anoptionally halogenated lower alkyl group, an arylalkyl group, aheteroarylalkyl group, an acyl group or an optionally protected carboxylgroup, or alternatively R⁹ and R¹⁰ together with the nitrogen atom towhich they are bonded may form a ring which may be substituted; and p isan integer of 0 to 6), an optionally substituted tetrazolyl group, anoptionally protected carboxyl group, an optionally substituted carbamoylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted imidazolyl group, a group of the formula: ##STR4## (whereinR¹³ represents a hydrogen atom or an optionally halogenated lower alkylgroup; and q is an integer of 0 to 2), or alternatively two substituentsselected from among R¹, R², R³ and R⁴ which are adjacent to each othermay form a ring together with the carbon atoms to which they are bondedrespectively;

R⁵ and R⁶ represent the same or different from each other, a hydrogenatom, a halogen atom, a hydroxy group, a cyano group, an optionallyhalogenated lower alkyl group or an optionally halogenated lower alkoxygroup; or alternatively R⁵ and R⁶ together with the carbon atoms towhich they are bonded respectively may form a cycloalkyl ring, anoxolane ring, a 1,3-dioxolane ring or a 1,4-dioxane ring;

W represents a group of the formula: --N═ or --CH═; R⁷ and R⁸ representthe same or different from each other, a hydrogen atom or an optionallyhalogenated lower alkyl group, or alternatively R¹ and R⁷ together withthe carbon atoms to which they are bonded respectively may form a ringwhich may contain a nitrogen atom, an oxygen atom or a sulfur atom andwhich may be substituted;

A represents a hydrogen atom, an optionally halogenated lower alkylgroup or a group of the formula: --X--(CH₂)_(m) --Z (wherein Xrepresents the formula: --CO--, --CS--, --CH₂ -- or --S(O)₂ --;

Z represents a hydroxy group, an optionally halogenated lower alkoxygroup, a cyano group, a halogen atom, an optionally protected carbamoylgroup, an optionally substituted aryl group, an optionally substitutedaryloxy group, an optionally substituted heteroaryl group, an optionallysubstituted heteroarylalkyloxy group, a group of formula: --NR¹¹ R¹²(wherein R¹¹ and R¹² represent the same or different from each other, ahydrogen atom, an optionally halogenated lower alkyl group, anoptionally substituted arylalkyl group, an optionally substitutedheteroarylalkyl group, an acyl group, an optionally protected carboxygroup or optionally substituted carbamoyl group, or alternatively R¹¹and R¹² together with the nitrogen atom to which they are bonded mayform a ring which may be substituted), or an optionally substitutedcycloalkyl group; and

m is an integer of 0 to 6);

Y represents an oxygen atom or a sulfur atom; and

n is an integer of 0 to 6!.

Anthranilic acid is o-aminobenzoic acid and the anthranilamide structureis essential structure to the compounds of the present invention.

In the above definition of the general formula (I), the lower alkylgroup consisting the optionally halogenated lower alkyl as defined withrespect to R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ andR¹⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms, andexamples thereof include methyl, ethyl, n-propyl, n-butyl, isopropyl,isobutyl, 1-methyl-propyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyland n-hexyl. Further, the term "optionally halogenated" means"substituted with one or more halogen atoms at any carbon atom(s)constituting the above lower alkyl group". Examples of the halogenated alower alkyl include trifluoromethyl group and a 2,2-dichloroethyl group.The most desirable examples of the optionally halogenated lower alkylinclude a methyl group, an ethyl group or a trifluoromethyl group.

The hydroxyalkyl as defined with respect to R¹, R², R³ and R⁴ is a groupcomposed of a lower alkyl group described above and a hydroxy groupbonded to any carbon atom thereof.

The cycloalkyl group as defined with respect to R¹¹ and R¹² is onehaving 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms.

The optionally halogenated lower alkoxy as defined with respect to R¹,R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² is one derived from the aboveoptionally halogenated lower alkyl group, and examples thereof includelower alkoxy groups such as a methoxy group and an ethoxy group; atrifluoromethyloxy group and a 2,2-dichloroethyloxy group.

The substituent constituting the "optionally substituted tetrazolyl","optionally substituted pyrazolyl" or "optionally substitutedimidazolyl" as defined with respect to R¹, R², R³ and R⁴ includes loweralkyl groups such as methyl, ethyl and t-butyl; lower alkyl groupssubstituted with one or more optionally substituted phenyl groups suchas p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,trityl and phenethyl; halogenated lower alkyl groups such as2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy lower alkylgroups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl,1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy loweralkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and1-palmitoyloxyethyl; lower alkoxycarbonyloxy lower alkyl groups such asmethoxycarbohyloxymethyl, 1-butoxycarbonyl-oxyethyl and1-(isopropoxycarbonyloxy)ethyl; carboxy lower alkyl groups such ascarboxymethyl and 2-carboxyethyl; heterocyclic groups such as3-phthalidyl; optionally substituted benzoyloxy lower alkyl groups suchas 4-glycyloxybenzoyloxymethyl and 4-N-(t-butoxycarbonyl)glycyloxy!benzoyloxymethyl; (substituted dioxolene)lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl;cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy lower alkylgroups such as 1-cyclohexyloxycarbonyloxyethyl.

The protecting group constituting the optionally protected carboxy asdefined with respect to R¹, R², R³, R⁴, R¹¹, R¹² and Z includes loweralkyl groups such as methyl, ethyl and t-butyl; lower alkyl groupssubstituted with optionally substituted phenyl groups such asp-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,trityl and phenethyl; halogenated lower alkyl groups such as2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy lower alkylgroups such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl,1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy loweralkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and1-palmitoyloxyethyl; lower alkoxycarbonyloxy lower alkyl groups such asmethoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and1-(isopropoxycarbonyloxy)ethyl; carboxy lower alkyl groups such ascarboxymethyl and 2-carboxyethyl; heterocyclic groups such as3-phthalidyl; optionally substituted benzoyloxy lower alkyl groups suchas 4-glycyloxybenzoyloxymethyl and 4-N-(t-butoxycarbonyl)glycyloxy!benzoyloxymethyl; (substituted dioxolene)lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl;cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy lower alkylgroups such as 1-cyclohexycoxylcarbonyloxyethyl.

Further, the protected group may be one of various acid amides, as faras it can be decomposed into a carboxyl group in vivo.

The acyl group as defined with respect to R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰,R¹¹ and R¹² includes those groups derived from aliphatic saturatedmonocarboxylic acids such as formyl, acetyl, propionyl and butyryl;those groups derived from aliphatic unsaturated carboxylic acids such asan acryloyl group, a propioloyl group, a methacryloyl group, a crotonoylgroup, an isocrotonoyl group, an oleoyl group and an elaidoyl group;those groups derived from carbocyclic carboxylic acids such as a benzoylgroup, a naphthoyl group, a toluoyl group, a hydratropoyl group and acinnamoyl group; those groups derived from heterocyclic carboxylic acidssuch as furoyl, thenoyl, nicotinoyl and isonicotinoyl; and those groupsderived from hydroxy carboxylic acids and alkoxy carboxylic acids suchas a glycoloyl group, a lactoyl group, a glyceroyl group, a tropoylgroup, a salicyloyl group, a veratroyl group, an anisoyl group and agalloyl group.

The above definition with respect to R⁹ and R¹⁰ or R¹¹ and R¹² that "R⁹and R¹⁰ (or R¹¹ and R¹²) together with the nitrogen atom to which theyare bonded may form a ring" means that they may together form apiperidine ring or a pyrrolidine ring.

Further, the above definition with respect to R¹ and R⁷ that "R¹ and R⁷together with the carbon atoms to which they are bonded respectively mayform a ring which may contain nitrogen, oxygen or sulfur" means that R¹and R⁷ may together form a ring condensed with the benzene ring to whichR¹ is bonded. Examples of the ring include piperidine, pyrrolidine,oxane, 1,3-dioxane and 1,4-dioxolane rings.

The optionally substituted aryl group as defined with respect to Zincludes a phenyl group, a naphthyl group and an anthranyl group.

The optionally substituted heteroaryl group as defined with respect to Zincludes a pyridyl group, a pyrrolyl group, an imidazolyl group, apyrazolyl group, a pyridazyl group, a pyrimidyl group, a pydidazylgroup, a furanyl group, a pyranyl group, a thienyl group, anisothiazolyl group, a furazanyl group, a quinazolyl group, an indolylgroup, a quinolyl group and a pyrazolidinyl group, though it is notlimited to them.

The aryl group constituting the optionally substituted arylalkyl asdefined with respect to R⁹, R¹⁰, R¹¹, R¹², R¹⁴ and Z is the same asdefined above. Further, the alkyl group constituting it may be onederived from the above lower alkyl. In the arylalkyl group, one to threearyl groups may be bonded to any carbon atoms of the alkyl group.

The heteroaryl constituting the optionally substituted heteroarylalkylgroup as defined with respect to R⁹, R¹⁰, R¹¹, R¹² and Z is the same asdefined above. The alkyl constituting it is a group derived from theabove lower alkyl group. In the heteroarylalkyl, one to threeheteroaryls may be bonded to any carbon atoms of the alkyl group.

The optionally substituted aryloxy group as defined with respect to Z isone derived from the above aryl, for example, phenoxy or naphthyloxy.

The heteroaryloxy group as defined with respect to Z is one derived fromthe above heteroaryl group.

Further, "the substituent" constituting the "an optionally substitutedaryl group", "an optionally substituted heteroaryl group", "anoptionally substituted arylalkyl group", "an optionally substitutedheteroarylalkyl group", "an optionally substituted aryloxy group", "anoptionally substituted heteroaryloxy group", "an optionally substitutedcarbamoyl group", "the substituent" which ring which may be substitutedthat is formed by R⁹, R¹⁰ and the nitrogen atom to which they are bondedhas, "the substituent" which ring which may be substituted that isformed by R¹¹, R¹² and the nitrogen atom to which they are bonded has,and "the substituent" which ring which may be substituted that is formedby R¹, R⁷ and the carbon atoms to which they are bonded has respectivelyincludes a hydroxy group; a cyano group; an amino group; a nitro group;halogen atoms such as a chlorine atom, a fluorine atom, a bromine atomand an iodine atom; lower alkyl groups such as methyl, ethyl andt-butyl; lower alkoxy groups such as methoxy, ethoxy and t-butoxy; anoptionally protected carboxyl group; a hydroxyalkyl group; acarboxyalkyl group; a tetrazolyl group and so forth.

Further, as described above, "R⁴ and R⁵ together with the nitrogen atomto which they are bonded may form a ring which may be substituted", andthe substituent represents the same as defined above.

The halogen atom as defined with respect to R⁶, R⁷ and Z includes afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The pharmacologically acceptable salt according to the present inventionincludes inorganic acid salts such as hydrochloride, sulfate,hydrobromide and phosphate; and organic acid salts such as formate,acetate, trifluoroacetate, maleate, fumarate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate.

Some compounds according to the present invention form hydrates and itis needless to say that these hydrates fall within the scope of thepresent invention.

Y is preferably an oxygen atom.

Main processes for the production of the compound of the presentinvention will now be described.

Preparation process 1

A compound represented by the general formula (I) wherein Y is an oxygenatom can be prepared by the following process: ##STR5## (wherein R¹ toR⁸, A and n are each as defined above)

Accordingly, this process is a process that an anthranilic acidderivative represented by the general formula (Ia) can be prepared bycondensing an anthranilic acid derivative represented by the generalformula (IIIa) with an amine represented by the general formula (V) in aconventional manner.

Although this condensation can be conducted in a conventional manner,the use of a condensing agent is preferable.

The condensing agent to be used in this process may be any conventionalone and examples thereof include N,N'-dicyclohexylcarbodiimlde,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation can be accelerated by the coexistence ofN-hydroxysuccinimide or N-hydroxybenztriazole.

The solvent to be used in the above condensation may be any organic oneinert to water and the condensation. Examples of such a solvent includeethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons suchas benzene, toluene and xylene; dichloromethene, chloroform,1,2-dichloroethane, acetonitrile, N,N-dimethylformamide and pyridine.

The reaction temperature may range from about 0° C. to the refluxingtemperature of the solvent.

Preparation process 2

A compound represented by the general formula (I) wherein A is a groupof the formula: --CO--(CH₂)_(m) -- Z (wherein Z and m are each asdefined above) can be prepared also by the following process: ##STR6##(wherein R¹ to R⁸, m, n and Z are each as defined above).

Accordingly, this is a process that an objective compound represented bythe general formula (Ib) can be prepared by reacting a compoundrepresented by the general formula (VI) with an anthranilic acidderivative represented by the general formula (VII).

The solvent to be used in this reaction may be any organic one inert tothe reaction, and examples thereof include ethers such as ether,tetrahydrofuran and 1,4-dioxane; hydrocarbons such as benzene, tolueneand xylene; dichloromethane, chloroform, 1,2-dichloro-ethane,acetonitrile, N,N-dimethylformamide and pyridine.

The reaction temperature may range from about -20° C. to the refluxingtemperature of the solvent.

The reaction can be accelerated by the use of an organic base such astriethylamine, diisopropyl-ethylamine or lutidine; or an inorganic basesuch as sodium hydrogencarconate, sodium carbonate, potassium carbonateor sodium hydroxide.

Preparation process 3

A compound represented by the general formula (I) wherein Z is acarboxyl group can be prepared by the following process: ##STR7##(wherein R¹ to R⁸, m and n are each as defined above; and Z' representsa protected carboxyl group)

Accordingly, this is a process that an objective compound represented bythe general formula (Ic') can be prepared by the hydrolysis of acompound represented by the general formula (Ic).

The solvent to be used in the hydrolysis may be any organic one inert tothe hydrolysis, and examples thereof include alcohols such as methanoland ethanol; and ethers such as tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Further, the existence of an inorganic base in the hydrolysis givesdesirable results, and example of the base include lithium hydroxide,sodium hydroxide, potassium hydroxide and barium hydroxide.

Preparation process 4

A compound represented by the general formula (I) wherein Z isrepresented by the formula: --NR¹¹ R¹² can be prepared also by thefollowing process: ##STR8## (wherein R¹ to R⁸, R¹¹, R¹², n and m areeach as defined above; and L represents a leaving group such as ahalogen atom, a p-toluenesulfonyloxy group or a methanesulfonyloxygroup).

Accordingly, this is a process that an objective compound represented bythe general formula (Id) can be prepared by reacting a compoundrepresented by the general formula (VII) with an amine represented bythe general formula (VIII).

The solvent to be used in the above reaction includes ethers such asether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol andethanol; dichloromethane; chloroform; 1,2-dichloroethane; acetonitrile;N,N-dimethylformamide; and dimethyl sulfoxide.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation Process 5

A compound represented by the general formula (I) wherein R⁸ is hydrogenand X is reprresented by the formula: --CH₂ -- can be prepared by thefollowing process: ##STR9## (wherein R¹ to R⁷, m, n and Z are each asdefined above).

Accordingly, this is a process that an objective compound represented bythe general formula (Ie) can be prepared by reacting a compoundrepresented by the general formula (IV) with a compound represented bythe general formula (V).

The above reaction may be conducted in a solvent inert to the reaction,and examples of such a solvent include ethers such as ether,tetrahydrofuran and 1,4-dioxane; hydrocarbons such as benzene, tolueneand xylene; acetonitrile; N,N-dimethylformamide; dimethyl sulfoxide;dichloromethane; chloroform; and 1,2-dichloroethane.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Further, the use of a catalytic amount of a base in the reaction givesdesirable results and examples of the base include4-dimethylaminopyridine and 4-pyrrolidinopyridine.

Preparation process 6

A compound represented by the general formula (I) wherein R⁸ and A areeach a hydrogen atom can be prepared also by the following process:##STR10## (wherein R¹ to R⁷ and n are each as defined above).

Accordingly, this is a process that an objective compound represented bythe general formula (If) can be prepared by reducing a compoundrepresented by the general formula (If') in a conventional manner.

This reduction can be conducted by any conventional process and examplesof the process include catalytic reduction with palladium/carbon orplatinum oxide, or reduction using a metal (such as iron, tin or zinc),reduction using an acid (such as hydrochloric or acetic acid) andreduction using stannic chloride.

The solvent to be used in the above reduction may be one inert to thereduction, for example, methanol or ethanol.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation Process 7

A compound represented by the general formula (IIIa) which is thestarting material of Preparation process 1 can be prepared by thefollowing process: ##STR11## (wherein R¹ to R⁴, R⁸ and A are each asdefined above; and R^(14') represents a group selected from among thosedefined with respect to R¹⁴ except hydrogen atoms).

Accordingly, a compound represented by the general formula (IIIa) can beprepared by deblocking a compound represented by the general formula(III).

When R¹⁴ is alkyl, it is preferable that a solvent inert to thedeblocking (such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane)be used in the presence of a base such as lithium hydroxide, sodiumhydroxide, potassium hydroxide or barium hydroxide at a temperatureranging from about 0° C. to the refluxing temperature of the solvent.

When R¹⁴ is benzyl, a compound represented by the general formula (IIIa)can be prepared by catalytic reduction using palladium/carbon or thelike as the catalyst.

Further, when R¹⁴ is 4-methoxybenzyl, benzhydryl or the like, thedeblocking can be conducted by the use of trifluoroacetic acid in asolvent such as dichloromethane, chloroform or 1,2-dichloroethane in thepresence of anisole. In this case, it is preferable that the reactiontemperature range from about 0° C. to the refluxing temperature of thesolvent.

Preparation process 8

A compound represented by the general formula (III) wherein X isrepresented by the formula: --CO--; m is 0; and R⁸ is a hydrogen atom,which is the starting material of Preparation process 7, can be preparedby the following process: ##STR12## (wherein Q and Q' each represent achlorine atom, a trichloromethoxy group or an imidazolyl group; and R¹to R⁴ and R¹¹ to R¹³ are each as defined above),

(1st step)

Accordingly, this step is that a compound represented by the generalformula (X) is prepared by reacting a compound represented by thegeneral formula (III') with a compound represented by the generalformula (IX).

In carrying out the above reaction, a solvent inert to the reaction maybe used, and examples of the solvent include ether, tetrahydrofuran,1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene,toluene and xylene.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

If necessary, a base such as triethylamine ordiisopropylethylamine maybe used in carrying out the above reaction to make the reaction proceedsmoothly.

The compound (X) prepared in this step may be used in the following 2ndstep without being isolated.

(2nd step)

This step is a step that a compound represented by the general formula(I'b) is prepared by reacting the compound (X) prepared in the above 1ststep with a compound represented by the general formula (VIII). Thereaction temperature preferably ranges from about 0° C. to the refluxingtemperature of the solvent.

Preparation process 9

Among the anthranilic acid derivatives (III') as the starting materialof Preparation process 8, an anthranilic derivative of free carboxylgroup (IIa') can be prepared by the following process: ##STR13##(wherein R¹ to R⁴ and R¹⁴ are each as defined above).

Accordingly, this process is that a compound represented by the generalformula (IIa') can be prepared by reacting a compound represented by thegeneral formula (IIa) with a compound represented by the general formula(XII).

The reaction is preferably conducted in a solvent such asN,N-dimethylformamide, acetonitrile, benzene, toluene, xylene,dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran or1,4-dioxane in the presence of a base such as sodium hydrogen-carbonate,sodium carbonate, potassium carbonate or cesium carbonate at atemperature ranging from about 0° C. to the refluxing temperature of thesolvent.

Preparation process 10

A compound represented by the general formula (VII) which is thestarting material of Preparation process 4 can be prepared by thefollowing process: ##STR14## (wherein Hal represents a halogen atom; Lrepresents a leaving group such as a halogen atom, ap-toluene-sulfonyloxy group or a methanesulfonyloxy group; and R¹ to R⁸,m, n and X are each as defined above).

Accordingly, this is a process that a compound represented by thegeneral formula (Id') can be prepared by reacting a compound representedby the general formula (Ia') with a compound represented by the generalformula (VI').

The solvent to be used in the reaction may be any one inert to thereaction and examples of such a solvent include ether, tetrahydrofuran,1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform,1,2-dichloroethane, acetonitrile, N,N-dimethylform-amide and pyridine.

The reaction temperature preferably ranges from -20° C. to the refluxingtemperature of the solvent.

Further, the coexistence of a base in the reaction gives desirableresults and examples of the base include organic ones such astriethylamine, diisopropylethylamine and lutidine; and inorganic onessuch as sodium hydrogencarbonate, sodium carbonate, potassium carbonateand sodium hydroxide.

Preparation process 11

A compound represented by the general formula (IV) which is the startingmaterial of Preparation process 5 can be prepared by the followingprocess: ##STR15## (wherein R¹ to R⁴, m, X, Hal and Z are each asdefined above).

Accordingly, this is a process that an objective compound (IV) can beprepared by reacting a compound represented by the general formula (XI)with sodium hydroxide, potassium hydride or the like, and reacting theresulting product with a compound represented by the general formula(VI').

In carrying out the reaction, a solvent inert to the reaction may beused, and examples of the solvent include N,N-dimethylformamide,N,N-dimethylacetamide and tetrahydrofuran.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation process 12

A compound represented by the general formula (If') which is thestarting material of Preparation process 6 can be prepared by thefollowing process: ##STR16## (wherein R¹ to R⁷ and n are each as definedabove).

Accordingly, this is a process that a compound represented by thegeneral formula (If') can be prepared by reacting a carboxylic acidrepresented by the general formula (IIa) or a reactive derivativethereof with a compound represented by the general formula (V) throughamidation. The reactive derivative of the compound (IIa) includes acidhalides such as acid chloride and acid bromide; acid azides; activeesters thereof with N-hydroxybenztriazole and N-hydroxysuccinimide; andmixed acid anhydrides thereof with p-toluenesulfonic acid and phosphoricacid ester.

When as a compound (IIa) free carboxylic acid is used, the reaction maybe conducted in the presence of a condensing agent such asN,N'-dicyclohexylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide or2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

In carrying out the reaction, an organic solvent inert to the reactionmay be used, and examples of the solvent include ether, tetrahydrofuran,1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform,1,2-dichloroethane, acetonitrile and N,N-dimethylformamide.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

When a certain reactive derivative is used, the addition of a base tothe reaction system gives desirable results, and examples of the baseinclude triethylamine, diisopropylethylamine, pyridine, lutidine, sodiumhydrogencarbonate, sodium carbonate and potassium carbonate.

Preparation process 13

A compound represented by the general formula (IIa) which is thestarting material of Preparation process 12 can be prepared by thefollowing process: ##STR17## (wherein R¹ to R⁴ and R¹⁴ are each asdefined above).

Accordingly, a compound represented by the general formula (IIa) can beprepared by deblocking a compound represented by the general formula(IIa').

The above reaction is preferably conducted in a solvent inert to thereaction (such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane) inthe presence of a base such as lithium hydroxide, sodium hydroxide,potassium hydroxide or barium hydroxide at a temperature ranging fromabout 0° C. to the refluxing temperature of the solvent.

Preparation process 14

A compound represented by the general formula (III') which is thestarting material of Preparation process 8 can be prepared by thefollowing process: ##STR18## (wherein R¹ to R⁴ and R¹⁴ are each asdefined above).

Accordingly, a compound represented by the general formula (III') can beprepared by condensing a compound represented by the general formula(IIIa') with a compound represented by the general formula (XII).

Although the condensation can be conducted by a conventional process theuse of a condensing agent is preferable. Examples of the condensingagent include N,N'-dicyclohexylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, though any conventionalcondensing agent can be used.

The reaction can be accelerated by the coexistence of4-dimethylaminopyridine or 4-pyrrolidinopyridine.

The reaction is preferably conducted in a solvent inert to the reactionsuch as acetonitrile, dichloromethane, chloroform orN,N-dimethylformamide at a temperature ranging from about 0° C. to therefluxing temperature of the solvent.

Preparation process 15

A compound represented by the general formula (III) wherein X isrepresented by the formula: --CO--; m is 0; R² is a cyano group; and R⁸is a hydrogen atom, which is the starting material of Preparationprocess 7, can be prepared by the following process: ##STR19## (whereinR¹, R³, R⁴ and R¹⁴ are each as defined above; M represents a metal atom;and p is an integer of 1 to 3).

Accordingly, a compound represented by the general formula (XIV) can beprepared by reacting a compound represented by the general formula(III") with a transition metal cyanide represented by the generalformula (XX).

The transition metal cyanide is preferably cuprous cyanide.

The reaction is preferably conducted either in the absence of anysolvent or in the presence of an organic solvent inert to the reactionsuch as pyridine, quinoline, N,N-dimethylformamide,N-methyl-2-pyrrolidone or HMPA at a temperature ranging from about 0° C.to the refluxing temperature of the solvent.

Preparation process 16

A compound represented by the general formula (V) in Preparation process1 wherein R⁷ is a hydrogen atom, can be prepared by the followingprocess: ##STR20## (wherein R⁵, R⁶ and n are each as defined above).

Accordingly, a compound represented by the general formula (V') can beprepared by deblocking a compound represented by the general formula(XIII). Although the deblocking may be conducted through acidic oralkaline hydrolysis, it is preferable to conduct the deblocking by theuse of hydrazine.

The solvent to be used in the above reaction may be any solvent inert tothe reaction, and examples of the solvent include methanol, ethanol,tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation process 17

A compound represented by the general formula (XIII) which is useful asthe starting material of Preparation process 16 can be prepared by thefollowing process: ##STR21## (wherein R⁵, R⁶, n and L are each asdefined above).

Accordingly, a compound represented by the general formula (XIII) can beprepared by reacting a compound represented by the general formula (XIV)with phthalimide represented by the formula (XV).

When L is a hydroxy group, a compound represented by the general formula(XIII) can be prepared by condensing a compound represented by thegeneral formula (XV) with phthalimide through the Mitsunobu reaction.Although this reaction can be conducted by a conventional process, itmay be conducted by the use of a phosphine compound such astriphenylphosphine and tributylphosphine and diethyl azocarboxylate oran azocarboxylic acid diester such as diethyl azocarboxylate.

The above reaction is preferably conducted in a solvent inert to thereaction such as tetrahydrofuran, 1,4-dioxane or acetonitrile at atemperature ranging from about 0° C. to the refluxing temperature of thesolvent.

When L is a leaving group such as a halogen atom, methanesulfonyloxy orp-toluenesulfonyloxy, a compound represented by the general formula(XIII) can be prepared by reacting a compound represented by the generalformula (XIV) with phthalimide or an alkali metal salt thereof. Thealkali metal salt of phthalimide includes sodium and potassium saltsthereof.

The solvent to be used in the reaction may be one inert to the reaction,and examples of such a solvent include acetonitrile,N,N-dimethylformamide, methanol, ethanol, tetrahydrofuran and1,4-dioxane.

When phthalimide is used, the reaction can be accelerated by the use ofan inorganic base such as sodium carbonate, sodium hydrogencarbonate orpotassium carbonate, or an organic base such as triethylamine,tributylamine or diazacycloundecene.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation process 18

A compound represented by the general formula (I) wherein Y is an oxygenatom and R¹ and R⁷ are combined together to form a ring can be preparedby the following process: ##STR22## (wherein R² to R⁶, n and L are eachas defined above).

Accordingly, a compound represented by the general formula (Ig), can beprepared by reacting a compound represented by the general formula (Ig')with a compound represented by the general formula (XVI).

It is preferable that the reaction be conducted in the presence of abase such as sodium hydride, potassium hydride or potassium t-butoxide.

The reaction is preferably conducted in a solvent inert to the reactionsuch as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide or N-methyl-2-pyrrolidone at a temperature ranging from about0° C. to the refluxing temperature of the solvent.

Preparation process 19

A compound represented by the general formula (Ig') which is thestarting material of Preparation process 18 can be prepared by thefollowing process: ##STR23## (wherein R² to R⁴, R¹⁴ and L are each asdefined above; and q is an integer of 1 to 6).

(1st step)

Accordingly, a compound represented by the general formula (XVIII) isprepared by reacting a compound represented by the general formula(XVII) with ammonia.

In carrying out the reaction, a solvent inert to the reaction may beused, and examples of the solvent include methanol, ethanol,tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

(2nd step)

Accordingly, a compound represented by the general formula (Ig') isprepared by reducing a compound represented by the general formula(XVIII) in a conventional manner.

The reduction can be conducted by a conventional process, and examplesof the process include catalytic reduction with palladium/carbon orplatinum oxide; reduction using a metal such as iron, tin or zinc and anacid such as hydrochloric acid or acetic acid; and reduction usingstannic chloride.

The solvent to be used in the reduction may be one inert to thereduction, for example, methanol or ethanol.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation process 20

A compound represented by the general formula (Ig') which is thestarting material of Preparation process 18 can be prepared also by thefollowing process: ##STR24## (wherein R² to R⁴, R¹⁴, L and q are each asdefined above).

(1st step)

Accordingly, a compound represented by the general formula (XVIII) isprepared by reacting a compound represented by the general formula(XVII) with a metal cyanide.

In carrying out the above reaction, a solvent inert to the reaction maybe used, and examples thereof include water, methanol, ethanol,tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide anddimethyl sulfoxide.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

(2nd step)

Accordingly, a compound represented by the general formula (Ig') isprepared by reducing a compound represented by the general formula(XVIII) in a conventional manner.

This reduction can be conducted by a conventional process, and examplesthereof include catalytic reduction with palladium/carbon or platinumoxide; reduction using a metal such as iron, tin or zinc and an acidsuch as hydrochloric or acetic acid; and reduction using stannicchloride.

The solvent to be used in the reduction may be one inert to thereduction, for example, methanol or ethanol.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

Preparation process 21

A compound represented by the general formula (Ig') wherein R² is ahalogen atom, which is the starting material of Preparation process 18,can be prepared by the following process: ##STR25## (wherein R³, R⁴ andX are each as defined above).

Accordingly, a compound represented by the general formula (Ig') can beprepared by halogenating a compound represented by the general formula(XIX) in a conventional manner.

This halogenation can be conducted by a conventional process, andexamples of the process include those using chlorine, bromine,tetra-n-butylammonium tribromide and benzyltrimethylammonium tribromide,respectively. The solvent to be used in the halogenation may be oneinert to the halogenation, for example, dichloromethane, chloroform oracetic acid.

The reaction temperature preferably ranges from about 0° C. to therefluxing temperature of the solvent.

The present invention also provides the following compounds:

those represented by the general formula (II) and pharmacologicallyacceptable salts thereof:

general formula (II) ##STR26## (wherein R¹, R², R³ and R⁴ are each asdefined above; R¹⁴ represents a hydrogen atom, an optionally halogenatedlower alkyl group or an optionally substituted arylalkyl group; and R¹⁵represents a nitro group or an amino group);

those represented by the general formula (III) and pharmacologicallyacceptable salts thereof:

general formula (III) ##STR27## (wherein R¹, R², R³, R⁴, R⁸, R¹⁴ and Aare each as defined above);

and

those represented by the general formula (IV) and pharmacologicallyacceptable salts thereof:

general formula (IV) ##STR28## (wherein R¹, R², R³, R⁴, m and Z are eachas defined above; and X² represents a group of the formula: --CH₂ --).

These compounds (II), (III) and (IV) are useful as intermediates forpreparing the compounds (I).

Pharmacological Experimental Example will now be described to illustratethe usefulness of the compounds of the present invention.

Pharmacological Experimental Example

Enzyme Inhibitory activity using cGMP-PDE prepared from porcine aorta

1. Experimental method

The enzyme activity of CGMP-PDE prepared from porcine aorta wasdetermined according to the method of Thompson et al. This determinationwas conducted in the presence of 1 mM EGTA by the use of 1 μM cGMP asthe substrate. Each compound according to the present invention wasdissolved in DMSO and added to the reaction system to determine theinhibitory activity thereof. The final concentration of DMSO in thereaction system was adjusted to 4% or below.

The cGMP-PDE was prepared as follows:

Porcine aorta was cut into fine pieces, followed by the addition of 10times by volume as much buffer A (20 mM Tris/HCl, 2 mM Mg acetate, 1 mMdithiothreitol, 5 mM EDTA, 1400TIU/1 aprotinin, 10 mg/1 leupeptin, 1 mMbenzamidine, 0.2 mM PMSF, pH7.5). The obtained mixture was homogenizedand centrifuged at 100,000×g for one hour. The obtained supernatant wasplaced on a column of DEAE-Toyopearl 650S (a product of Tosoh, Tokyo,Japan), followed by the washing of the column with buffer B (50 mMTris/HCl, 0.1 mM EGTA, 2 mM Mg acetate, 1 mM Dithiothreitol, 0.2 mMPMSF, pH7.5). The resulting column was subjected to gradient elutionwith 0.05 to 0.4M sodium chloride to obtain CaM-independent cGMP-PDEfractions.

2. Experimental results

The cGMP-PDE inhibitory activities of compounds of the present inventionthus determined are given in Table 1, wherein a lower IC₅₀ valueexhibits a more remarkable effect.

                  TABLE 1                                                         ______________________________________                                               Ex. No.                                                                             IC.sub.50 (nM)                                                   ______________________________________                                               9     28.8                                                                    19    16.6                                                                    33    20.5                                                                    38    6.7                                                                     39    3.2                                                                     41    1.4                                                                     43    0.9                                                                     44    79.8                                                                    45    0.7                                                                     47    5.3                                                                     74    2.4                                                                     80    11.9                                                                    81    14.5                                                                    83    12.6                                                                    85    21.7                                                                    109   4.4                                                                     110   0.7                                                                     111   2.0                                                                     112   5.3                                                                     113   0.4                                                                     114   1.7                                                                     115   24.8                                                                    116   2.9                                                                     117   11.5                                                                    120   21.5                                                                    121   7.7                                                                     122   5.0                                                                     123   6.1                                                                     125   19.2                                                                    126   2.9                                                                     129   36.8                                                                    136   18.1                                                                    141   7.2                                                              ______________________________________                                    

It can be understood from the results of the above PharmacologicalExperimental Example that the compound of the present invention has aninhibitory activity against PDE, particularly cGMP-PDE. In other words,it can be understood that the compound of the present invention exhibitsan effect of increasing the in vivo concentration of cGMP through itsinhibitory activity against cGMP-PDE. Accordingly, the anthranilic acidderivative of the present invention is effective in the prevention andtreatment of diseases wherein a cGMP-PDE inhibitory action isefficacious. Examples of such diseases include ischemic heart diseasessuch as angina pectoris, myocardial infarction, and chronic and acuteheart failure; pulmonary hypertension accompanied and not accompanied bycot pulmonale; hypertension due to various causes; peripheralcirculation failure; brain circulatory failure; cerebral dysfunction;and allergic diseases such as bronchial asthma, atopic dermatitis andallergic rhinitis.

Further, the compound of the present invention is less toxic and highlysafe, thus being valuable also in this sense.

The present invention provides a preventive and therapeutic agent fordiseases wherein a phosphodiesterase inhibitory action is efficacious,which comprises an anthranilic acid derivative or pharmacologicallyacceptable salt thereof as described above as an active ingredient; anda preventive and therapeutic agent for diseases wherein a cyclic GMPphosphodiesterase inhibitory action is efficacious, which comprises ananthranilic acid derivative or pharmacologically acceptable salt thereofas described above as an active ingredient.

The compound of the present invention is particularly efficaciousagainst ischemic heart diseases, angina pectoris, hypertension,pulmonary hypertension, heart failure and asthma.

Further, the present invention provides a drug composition comprising apharmacologically effective amount of an anthranilic acid derivative orpharmacologically acceptable salt thereof as described above and apharmacologically acceptable carrier; and a method for the preventionand treatment of diseases which comprises administering apharmacologically acceptable amount of an anthranilic acid derivative orpharmacologically acceptable salt thereof as described above to inhibitphosphodiesterase.

The compound of the present invention is administered as a drug orallyor parenterally. The dose thereof varies depending upon the extent ofsympton; the age, sex, weight and drug sensitivity of patient;dosage-regimen; dosing timing; dosing interval; the kind of preparation;the drug to be administered together therewith; the kind of the activeingredient and so on, being not particularly limited.

In the oral administration, the dose per adult a day is generally about0.1 to 1000 mg, preferably about 5 to 500 mg, which may be administeredin one to three portions a day.

In the administration as an injection, the dose a day is generally about1 μg/kg to 3000 μg/kg, preferably about 3 μg/kg to 1000 μg/kg.

A solid preparation for oral administration according to the presentinvention is prepared by adding a filler and, if necessary, a binder,disintegrator, lubricant, color and/or corrigent to an active ingredientand shaping the obtained mixture into a tablet, coated tablet, granule,powder or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide; those of the binderinclude polyvinyl alcohol, polyvinyl ether, ethylcellulose,methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin; those of the lubricant include magnesium stearate,talc, polyethylene glycol, silica and hardened vegetable oil; those ofthe color include those authorized as pharmaceutical additives; andthose of corrigent include cocoa powder, menthol, aromatic powder,mentha oil, borneol and powdered cinnamon bark. Of course, the tabletand granule may be suitably coated with sugar, gelatin or the like, ifnecessary.

When an injection according to the present invention is prepared, a pHregulator, buffer, suspending agent, solubilizing agent, stabilizer,isotonicity and/or preservative may be added to an active ingredient atneed and formulating the mixture into an injection for intravenous,subcutaneous or intramuscular administration in a conventional manner.Further, the injection may be freeze-dried at need.

Examples of the suspending agent include methylcellulose, Polysorbate80, hydroxyethylcellulose, acacia, tragacanth powder,carboxymethylcellulose sodium, and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizing agent include polyoxyethylene hardenedcastor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitanmonolaurate, Macrogol, and ethyl ester of castor oil fatty acid.

Examples will now be described to facilitate the understanding of thepresent invention, though they are preceded by Preparative Examples assynthesis examples wherein starting material compounds to be used in thepreparation of the compounds of the present invention are prepared.

Preparative Example 1

Ethyl 1- (2-Carboxy-4-chlorophenyl-1)carbamoyl!-piperidine-4-carboxylate ##STR29##

Anisole (4.7 ml) was added to 4.09 g of ethyl 1- 4-chloro-2-(4-methoxybenzyloxy)carbonyl!phenyl!-carbamoyl!piperidine-4-carboxylate,followed by the dropwise addition of 6.6 ml of trifluoroacetic acid. Theobtained mixture was stirred at room temperature for one hour andconcentrated, followed by the addition of ether. The resulting mixturewas extracted with a saturated aqueous solution of sodiumhydrogencarbonate. The pH of the aqueous phase was adjusted to about 2with concentrated hydrochloric acid to precipitate crystals. Thecrystals were recovered by filtration and washed with water to give 2.09g of the title compound as a white powder (yield: 69%).

M.P.: 159° to 160° C. (dec.) (white needle aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.27(t, J=7.1Hz, 3H), 1.78(m, 2H), 2.02(m, 2H), 2.58(m, 1H), 3.10(m,2H), 4.11(m, 2H), 4.18(q, J=7.1Hz, 2H), 7.47(dd, J=2.7, 9.2Hz, 1H),8.01(d, J=2.7Hz, 1H), 8.47(d, J=9.2Hz, 1H), 10.70(s, 1H)

Preparative Example 2

Ethyl 1-4-chloro-2-(4-methoxybenzyloxy)-carbonylphenyl!carbamoyl!piperidine-4-carboxylate##STR30##

4-Methoxybenzyl 2-amino-5-chlorobenzoate (20.74 g) was dissolved in 180ml of tetrahydrofuran, followed by the addition of 12.69 g of1,1'-carbonyldiimidazole. The obtained mixture was heated under refluxfor 43 hours and cooled by allowing to stand, followed by the additionof 12.06 ml of ethyl isonipecotate. The obtained mixture was allowed tostand at room temperature for one hour, followed by concentration. Waterwas added to the obtained concentrate, followed by the extraction withethyl acetate. The organic phase was washed with 1N hydrochloric acid, asaturated aqueous solution of sodium hydrogencarbonate, and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate, and distilled to remove the solvent.Benzene-insoluble matters were filtered out and the filtrate waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate (3:1)) to give 11.07 g of the title compound as a yellow oil(yield: 334).

NMR(400MHz, δ, CDCl₃)

1.27(t, J=7.1Hz, 3H), 1.76(m, 2H), 2.01(m, 2H), 2.54(m, 1H), 3.07(m,2H), 3.83(s, 3H), 4.12(m, 2H), 4.32(q, 7.1Hz, 2H), 5.28(s, 2H),6.91-6.96(m, 2H), 7.36-7.40(m, 2H), 7.43(dd, J=2.6, 9.2Hz, 1H), 7.95(d,J=2.6Hz), 8.66(d, J=9.2Hz), 10.68(s, 1H)

Preparative Example 3

4-Methoxybenzyl 2-amino-5-chlorobenzoate ##STR31##

2-Amino-5-chlorobenzoic acid (15.00 g), methoxybenzyl chloride (13.1 ml)and potassium carbonate (13.3 g) were added to N,N-dimethylformamide(175 ml). The obtained mixture was stirred at room temperature for 43hours, followed by the addition of ice-water. The resulting mixture wasextracted with ethyl acetate. The organic phase was washed with waterand a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and distilled to remove the solvent. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate (5:1)) to give 20.97 g of the title compound as a pale-yellowoil (yield: 82%).

NMR(400MHz, δ, CDCl₃)

3.82(s, 3H), 5.24(s, 2H), 5,74(br, 2H), 6.59(d, J=8.8Hz, 1H),6.89-6.94(m, 2H), 7.18(dd, J=2.6, 8.8Hz, 1H), 7.34-7.39(m, 2H), 7.82(d,J=2.6Hz, 1H)

Preparative Example 4

Methyl 2-amino-5-dimethylaminomethylbenzoate ##STR32##

Methyl 5-dimethylaminomethyl-2-nitrobenzoate (12.92 g) and stannouschloride dihydrate (60.39 g) were added to 110 ml of ethanol. Theobtained mixture was stirred at 70° C. for one hour, followed by theaddition of ice-water. The resulting mixture was alkalified with sodiumcarbonate and extracted with ethyl acetate. The organic phase was driedover anhydrous magnesium sulfate and distilled to remove the solvent.The residue was purified by silica gel chromatography (solvent:dichloromethane/methanol (30:1 to 10:1)) to give 10.93 g of the titlecompound as a pale-yellow oil (yield: 97%).

NMR(400MHz, δ, CDCl₃)

2.20(s, 6H), 3.29(s, 2H), 3.85(s, 3H), 5.68(br, 2H), 6.63(d, J=8.4Hz,1H), 7.22(dd, J=2.2, 8.4Hz, 1H), 7.74(d, J=2.2Hz, 1H)

Preparative Example 5

Methyl 5-dimethylaminomethyl-2-nitrobenzoate ##STR33##

Methyl 5-methyl-2-nitrobenzoate (8.06 g) was dissolved in 140 ml ofcarbon tetrachloride, followed by the addition of 7.72 g ofN-bromosuccinimide and 0.50 g of benzoyl peroxide. The obtained mixturewas heated under reflux for 5 hours and filtered to remove insolubles.The filtrate was concentrated to give a yellow oil. This oil wasdissolved in 80 ml of acetonitrile, followed by the addition of 4.04 gof dimethylamine hydrochloride and 6.86 g of potassium carbonate. Theobtained mixture was stirred at room temperature for 5 hours andconcentrated, followed by the addition of water. The resulting mixturewas extracted with ethyl acetate. The organic phase was dried overanhydrous magnesium sulfate and distilled to remove the solvent. Theresidue was purified by silica gel column chromatography (solvent:dichloro-methane/methanol (30:1)) to give 3.17 g of the title compoundas a yellow oil (yield: 32%).

NMR(400MHz, δ, CDCl₃)

2.26(s, 6H), 3.51(s, 2H), 3.93(s, 3H), 7.59(dd, J=1.8, 8.4Hz, 1H),7.68(d, J=1.8Hz, 1H), 7.91(d, J=8.4Hz, 1H)

Preparative Example 6

6-Chloro-1-4-(ethoxycarbonyl)butyl!-1,2-dihydro-4H-1,3-benzoxazine-2,4-dione##STR34##

1.11 g of 60% sodium hydride (suspended in mineral oil) was suspended in80 ml of N,N-dimethylacetamide, followed by the addition of 5.00 g of6-chloro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione in portions. Theobtained mixture was stirred at room temperature for one hour, followedby the addition of 4.81 ml of ethyl 5-bromovalerate. The obtainedmixture was stirred at 50° C. for 24 hours and poured onto 200 ml of 1Nhydrochloric acid/ice, followed by the extraction with ethyl acetate.The organic phase was washed with water and a saturated aqueous solutionof common salt, dried over anhydrous magnesium sulfate, and distilled toremove the solvent. Ether was added to the obtained solid residue andthe resulting mixture was filtered to give 4.89 g of the title compoundas a pale-yellow powder (yield: 60%).

M.P.: 97° to 99° C.

(slightly yellow needle from n-Hex/EtOAc)

NMR(400MHz, δ, CDCl₃)

1.25(t, J=7.1Hz, 3H), 1.72-1.86(m, 4H), 2.40(t, J=7.0Hz, 2H), 4.07(t,J=7.3Hz, 2H), 4.13(q, J=7.1Hz, 2H), 7.17(d, J=9.0Hz, 1H), 7.71(dd,J=2.6, 9.0Hz, 1H), 8.12(d, J=2.6Hz, 1H)

Preparative Example 7

6-Chloro-1-3-(ethoxycarbonyl)propyl!-1,2-dihydro-4H-1,3-benzoxazine-2,4-dione##STR35##

A pale-yellow powder was prepared (yield: 60%).

M.P.: 78° to 80° C.

(pale-yellow prism from n-Hex/EtOAc)

NMR(400MHz, δ, CDCl₃)

1.30(t, J=7.1Hz, 3H), 1.99-2.09(m, 2H), 2.51(t, J=6.2Hz, 2H), 4.12(t,J=8.1Hz, 2H), 4.19(q, J=7.1Hz, 2H), 7.52(d, J=9.0Hz, 1H), 7.75(dd,J=2.4, 9.0Hz, 1H), 8.12(d, J=2.4Hz, 1H)

Preparative Example 8

6-Chloro-1-4-(methoxycarbonyl)benzyl!-1,2-dihydro-4H-1,3-benzoxazine-2,4-dione##STR36##

A slightly yellow powder was prepared (yield: 89%).

M.P.: 214° to 217° C. (white needle from EtOAc)

NMR(400NHz, δ, CDCl₃)

3.91(s, 3H), 6.97(d, J=9.0Hz, 1H), 7.33-7.38(m, 2H), 7.57(dd, J=2.6,9.0Hz, 1H), 8.02-8.06(m, 2H), 8.14(d, J=2.6Hz)

Preparative Example 9

4-Methoxybenzyl 2-amino-5-bromobenzoate ##STR37##

2-Amino-5-bromobenzoic acid (15.59 g), 4-methoxybenzyl alcohol (7.5 ml),1,3-dicyclohexylcarbodiimide (14.89 g) and 4-dimethylaminopyridine (8.07g) were added to 200 ml of acetonitrile. The obtained mixture wasstirred at room temperature for 18 hours and filtered to removeinsolubles. The filtrate was concentrated in a vacuum, followed by theaddition of water. The resulting mixture was extracted with ethylacetate. The ethyl acetate phase was washed with water, IN hydrochloricacid, water, 1N sodium hydroxide, water, and a saturated aqueoussolution of common salt successively, dried over anhydrous magnesiumsulfate, and distilled in a vacuum to remove the solvent. The residuewas purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (8:1 to 5:1)) to give 13.13 g of the titlecompound as a pale-yellow oil (yield: 65%).

¹ H-NMR(400MHz, CDCl₃) δ:

3.82(3H, s), 5.24(2H, s), 5.76(2H, br s), 6.54(1H, d, J=8.8Hz), 6.92(2H,m), 7.30(1H, dd, J=8.8, 2.6Hz), 7.37(2H, m), 7.96(1H, d, J=2.6Hz)

Preparative Example 10

4-Methoxybenzyl 2-amino-5-cyanobenzoate ##STR38##

2-Amino-5-cyanobenzoic acid (32.18 g), 4-methoxybenzyl chloride (28.34ml) and anhydrous potassium carbonate (28.89 g) were added to 400 ml ofN,N-dimethylformamide. The obtained mixture was stirred at roomtemperature for 15 hours, followed by the addition of ice-water. Theresulting mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with water, 1N hydrochloric acid, water, a saturatedaqueous solution of sodium hydrogencarbonate, water, and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate, and distilled in a vacuum to remove the solvent. Theresidue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (4:1 to 3:1)). The obtained solid was washed witha n-hexane/ethyl acetate mixture to give 28.92 g of the title compoundas a pale-yellow powder (yield: 52%).

M.P.: 120°-122° C.

MASS: 283(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.83(3H, s), 5.26(2H, s), 6.30(2H, br s), 6.65(1H, d, J=8.6Hz),6.91-6.98(2H, m), 7.35-7.40(2H, m), 7.43(1H, dd, J=8.6, 2.0Hz), 8.19(1H,d, J=2.0Hz)

Preparative Example 11

Ethyl 1- 4-bromo-2-(4-methoxybenzyloxy)carbonyl!phenyl!carbamoyl!piperidine-4-carboxylate##STR39##

4-Methoxybenzyl 2-amino-5-bromobenzoate (13.13 g) and1,1'-carbonyldiimidazole (6.97 g) were added to 100 ml oftetrahydrofuran. The obtained mixture was heated under reflux for 41hours and cooled by allowing to stand, followed by the addition of 6.63ml of ethyl isonipecotate. The obtained mixture was stirred at roomtemperature for one hour and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate (3:1)) to give 4.40 g of the title compound as a pale-yellowsolid (yield: 20%).

M.P.: 98° to 100° C.

MASS: 520(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.27(3H, t, J=7.1Hz), 1.76(2H, m), 2.01(2H, m), 2.55(1H, m), 3.07(2H,m), 3.83(3H, s), 4.12(2H, m), 4.17(2H, q, J=7.1Hz), 5.28(2H, s),6.94(2H, m), 7.38(2H, m), 7.56(1H, dd, J=9.2, 2.6Hz), 8.09(1H, d,J=2.6Hz), 8.46(1H, d, J=9.2Hz), 10.69(1H, s)

Preparative Example 12

1- 4-Chloro-2-(4-methoxybenzyloxy)carbonyl!phenyl!carbamoyl!-4-hydroxypiperidine##STR40##

The title compound was prepared as a white solid in a similar manner tothat of Preparative Example 3 (yield: 4%).

M.P.: 112° to 114° C.

MASS: 419(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.55-1.65(3H, m), 1.98(2H, m), 3.27(2H, ddd, J=13.7, 9.2, 3.3Hz),3.83(3H, s), 3.91-4.00(3H, m), 5.28(2H, s), 6.91-6.96(2H, m),7.35-7.40(2H, m), 7.43(1H, dd, J=9.2, 2.6Hz), 7.95(1H, d, J=2.6Hz),8.52(1H, d, J=9.2Hz), 10.69(1H, s)

Preparative Example 13

1- 4-Cyano--2-(4-methoxybenzyloxy)carbonyl!-phenyl!carbamoyl!-4-hydroxypiperidine##STR41##

The title compound was prepared as a white solid in a similar manner tothat of Preparative Example 3 (yield: 4%).

M.P.: 167° to 169° C.

MASS: 410(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.56-1.67(3H, m), 1.99(2H, m), 3.33(2H, ddd, J=13.7, 9.0, 3.5Hz),3.84(3H, s), 3.91-4.03(3H, m), 5.31(2H, s), 6.92-6.97(2H, m),7.35-7.40(2H, m), 7.69(1H, dd, J=9.0, 2.2Hz), 8.30(1H, d, J=2.2Hz),8.69(1H, d, J=9.0Hz), 11.04(1H, s)

Preparative Example 14

Ethyl 1- (4-bromo-2-carboxyphenyl)carbamoyl!piperidine-4-carboxylate##STR42##

A mixture comprising 3.82 g of ethyl 1- 4-bromo-2-(4-methoxybenzyloxy)carbonyl!phenyl!carbamoyl!-piperidine-4-carboxylate,4.02 ml of anisole and 5.7 ml of trifluoroacetic acid was stirred atroom temperature for 2.5 hours and concentrated in a vacuum. An aqueoussolution of sodium carbonate and ether were added to the residue torecover the aqueous phase. The ethereal phase was extracted with anaqueous solution of sodium carbonate. Both of the aqueous phases werecombined and washed with ether. The resulting aqueous phase wasacidified with concentrated hydrochloric acid to give precipitates. Theprecipitates were recovered by filtration to give 2.50 g of the titlecompound as a white powder (yield: 85%).

M.P.: 153° to 155° C. (dec.)

MASS: 399(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.28(3H, t, J=7.1Hz), 1.77(2H, m), 2.02(2H, m), 2.58(1H, m), 3.09(2H,m), 4.11(2H, m), 4.18(2H, q, J=7.1Hz), 7.61(1H, dd, J=9.2, 2.6Hz),8.16(1H, d, J=2.6Hz), 8.42(1H, d, J=9.2Hz), 10.67(1H, s)

Preparative Example 15

1- (2Carboxy-4-chlorophenyl)carbamoyl!-4-hydroxypiperidine ##STR43##

The title compound was obtained as a white solid in a similar manner tothat of Preparative Example 6 (yield: 77%).

M.P.: 168° to 170° C. (dec.)

MASS: 299(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

1.36(2H, m), 1.78(2H, m), 3.16(2H, ddd, J=13.5, 9.5, 3.1Hz),3.67-3.83(3H, m), 7.57(1H, dd, J=9.2, 2.7Hz), 7.89(1H, d, J=2.7Hz),8.43(1H, d, J=9.2Hz), 10.85(1H, s)

Preparative Example 16

1- (2Carboxy-4-cyanophenyl)carbamoyl!-4-hydroxypiperidine ##STR44##

The title compound was obtained as a white solid in a similar manner tothat of Preparative Example 6 (yield: 77%).

M.P.: 175° to 179° C. (dec.)

MASS: 290(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

1.37(2H, m), 1.78(2H, m), 3.19(2H, ddd, J=13.2, 9.3, 3.5Hz),3.68-3.82(3H, m), 7.93(1H, dd, J=9.0, 2.2Hz), 8.30(1H, d, J=2.2Hz),8.55(1H, d, J=9.0Hz), 11.23(1H, s)

Preparative Example 17

Methyl 2-amino-5-bromo-4-methoxybenzoate ##STR45##

Methyl 2-amino-4-methoxybenzoate (8.44 g) and calcium carbonate (5.13 g)were dissolved in a solvent mixture comprising 250 ml of dichloromethaneand 100 ml of methanol, followed by the addition of 19.09 g ofbenzyltrimethylammonium tribromide in portions. The obtained mixture wasstirred at room temperature for one hour and filtered to removeinsolubles. The filtrate was concentrated in a vacuum. Ethyl acetate wasadded to the residue and the obtained mixture was filtered throughsilica gel. The filtrate was concentrated in a vacuum and the residuewas purified by silica gal column chromatography (solvent:n-hexane/ethyl acetate (4:1)). The obtained solid was washed withn-hexane to give 10.37 g of the title compound as a pale-yellow solid(yield: 86%).

M.P.: 104° to 105° C.

MASS: 260 (MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.84(3H, s), 3.87(3H, s), 5.85(2H, br, s), 6.12(1H, s), 8.01(1H, s)

Preparative Example 18

7Nitroisoindoline-1-one ##STR46##

Methyl 2-bromomethyl-5-nitrobenzoate (6.59 g) was suspended in 180 ml ofmethanol. A large excess of ammonia was passed through the obtainedsuspension at room temperature. The resulting mixture was stirred atroom temperature for 20 hours and concentrated in a vacuum. Water wasadded to the residue and the obtained mixture was filtered to recover aninsoluble matter, which was washed with ether. The title compound (3.88g) was obtained as a slightly yellow powder (yield: 90%).

M.P.: 218° to 221° C.

MASS: 179(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

4.48(2H, s), 7.80(1H, dd, J=7.7, 7.3Hz), 7.87(1H, d, J=7.3Hz), 7.88(1H,d, J=7.7Hz), 8.98(1H, br s)

Preparative Example 19

7Aminoisoindoline-1-one ##STR47##

7-Nitroisoindoline (6.52 g) was suspended in 1000 ml of tetrahydrofuran,followed by the addition of 1 g of 10% palladium/carbon(water-containing one). The obtained mixture was subjected to catalyticreduction under the conditions of room temperature and one atm. After 18hours, the catalyst was filtered out and the filtrate was concentratedin a vacuum. The obtained solid was washed with ether to give 5.13 g ofthe title compound as a slightly yellow powder (yield: 95%).

M.P.: 153° to 155° C.

MASS: 149(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

4.36(2H, s), 5.21(2H, br s), 6.57(1H, d, J=8.1Hz), 6.70(1H, d, J=7.3Hz),6.72(1H, br s), 7.27(1H, dd, J=8.1, 7.3Hz)

Preparative Example 20

Methyl 2-cyanomethyl-6-nitrobenzoate ##STR48##

Methyl 2-bromomethyl-5-nitrobenzoate (11.64 g) was suspended in 200 mlof methanol, followed by the addition of a solution of 2.19 g of sodiumcyanide in 20 ml of water. The obtained mixture was stirred at 50° C.for 3 hours and concentrated in a vacuum. Water was added to the residueand the resulting mixture was extracted with ethyl acetate. The organicphase was washed with water and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate, and concentrated in avacuum. The residue was purified by silica gel column chromatography(solvent: n-hexane/ethyl acetate (3:1 to 2:1)). The obtained solid waswashed with n-hexane to give 5.43 g of the title compound as a whitesolid (yield: 58%).

M.P.: 103° to 105° C.

MASS: 221(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.91(2H, s), 3.98(3H, s), 7.68(1H, t, J=8.1Hz), 7.87(1H, dd, J=8.1,1.1Hz), 8.11(1H, dd, J=8.1, 1.1Hz )

Preparative Example 21

8-Amino-1,2,3,4-tetrahydro-1-isoquinolinone ##STR49##

Methyl 2-cyanomethyl-5-nitrobenzoate (54.43 g) was suspended in 200 mlof methanol, followed by the addition of 4.5 ml of concentratedhydrochloric acid and 0.18 g of platinum oxide. The obtained mixture wassubjected to catalytic reduction under the conditions of roomtemperature and 3 kg/cm². After 7 hours the catalyst was filtered outand the filtrate was concentrated in a vacuum.

The residue was dissolved in 50 ml of methanol, followed by the additionof 7.50 g of anhydrous potassium carbonate. The obtained mixture washeated under reflux for 9.5 hours and filtered to remove insolubles. Thefiltrate was concentrated in a vacuum, followed by the addition ofwater. The resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with water and a saturated aqueous solution ofcommon salt, dried over anhydrous magnesium sulfate, and concentrated ina vacuum. The residue was purified by silica gel column chromatography(solvent: dichloromethane/methanol (30:1)) to give 0.75 g of the titlecompound as a white solid (yield: 19%).

M.P.: 128° to 130° C.

MASS: 163 (MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

2.90(2H, t, J=6.6Hz), 3.47(1H, dt, J=6.6, 2.9Hz), 5.98(1H, br s),6.05(2H, br s), 6.43(1H, dd, J=7.3, 1.1Hz), 6.52(1H, dd, J=8.3, 1.1Hz),7.12(1H, dd, J=8.1, 7.3Hz)

Preparative Example 22

7Amino-4-bromoisoindoline-1-one ##STR50##

The title compound was obtained as a white powder in a similar manner tothat of Preparative Example 9 (yield: 82%).

M.P.: 253° to 258° C. (dec.)

MASS: 227(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

4.12(2H, s), 6.20(2H, br s), 6.56(1H, d, J=8.6Hz), 7.32(1H, d, J=8.6Hz),8.38(1H, br s)

Preparative Example 23

7-Amino-4-bromoispindoline-1-one ##STR51##

The title compound was obtained as a white powder in a similar manner tothat of Preparative Example 9 (yield: 68%).

M.P.: 158° to 180° C. (dec.)

MASS: 241(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.01(2H, t, J=6.6Hz), 3.48(2H, dt, J=6.6, 2.9Hz), 6.13(2H, br s),6.19(1H, br s), 6.45(1H, d, J=8.8Hz), 7.32(1H, d, J=8.8Hz)

Preparative Example 24

Methyl 2-amino-5-cyanobenzoate ##STR52##

Methyl 2-amino-5-bromobenzoate (5.00 g) was dissolved in 10 ml ofN-methyl-2-pyrrolidone, followed by the addition of 2.14 g of cuprouscyanide. The obtained mixture was stirred at 180° C. for 4 hours,followed by the addition of an aqueous solution of ethylenediamine. Theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with water and a saturated aqueous solution of common salt,dried over anhydrous magnesium sulfate, and concentrated in a vacuum.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (3:1 to 2:1)). The obtained solid was washed withn-hexane to give 2.84 g of the title compound as a slightly yellowpowder (yield: 74%).

M.P.: 127° to 130° C.

MASS: 177(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.90(3H, s), 6.30(2H, br s), 6.67(1H, d, J=8.8Hz), 7.45(1H, dd, J=8.6,2.0Hz), 8.20(1H, d, J=2.0Hz)

Preparative Example 25

2-Amino-5-cyanobenzoic acid ##STR53##

Methyl 2-amino-5-cyanobenzoate (2.84 g) was dissolved in 60 ml ofethanol, followed by the addition of 24 ml of 1N sodium hydroxide. Theobtained mixture was stirred at room temperature for 6 hours andconcentrated in a vacuum. Water and ether were added to the residue andthe resulting aqueous phase was recovered. The ethereal phase wasextracted with water. Both of the aqueous phases were combined andacidified with concentrated hydrochloric acid to give precipitates,which were recovered by filtration. The title compound (2.55 g) wasobtained as a white powder (yield: 98%).

M.P.: 268° to 272° C.

MASS: 163(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

6.85(1H, d, J=8.8HZ), 7.49(2H, br s), 7.55(1H, dd, J=8.8, 2.2Hz),8.03(1H, d, J=2.2Hz)

Preparative Example 26

2-Amino-5-(1,2,4-triazol-1-yl)benzoic acid ##STR54##

Ethyl 2-amino-5-(1,2,4-triazol-1-yl)benzoate (2.00 g) was suspended in15 ml of ethanol, followed by the addition of 9.2 ml of 1N sodiumhydroxide. The obtained mixture was stirred at 65° C. for one hour andconcentrated in a vacuum. Water was added to the residue and theresulting mixture was acidified with concentrated hydrochloric acid togive precipitates. The precipitates were recovered by filtration to give2.55 g of the title compound as a slightly yellow powder (yield: 100%).

M.P.: 229° to 231° C.

MASS: 235 (MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

8.24-8.27(2H, m), 8.34(1H, m), 8.36(1H, s), 9.57(1H, s)

Preparative Example 27

2-Amino-5-(1-pyrazolyl)benzoic acid ##STR55##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Preparative Example 18 (yield: 100%).

M.P.: 246° to 248° C.

MASS: 234(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

6.67(1H, dd, J=2.6, 1.8Hz), 7.90(1H, d, J=1.8Hz), 8.18-8.24(2H, m),8.27(1H, m), 8.79(1H, d, J=2.6Hz)

Preparative Example 28

2-Amino-5-bromo-4-methoxybenzoic acid ##STR56##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Preparative Example 17 (yield: 97%).

M.P.: 198° C. (dec.)

MASS: 245(MH⁺)

¹ H-NMR(400MHz, DMSO-d₆) δ:

3.80(3H, s), 6.42(1H, s), 7.71(1H, s)

Preparative Example 29

5-Chloro-2-chloroacetamido-N-(3-chloro-4-methoxybenzyl)benzamide##STR57##

2-Amino-5-chloro-N-(3-chloro-4-methoxybenzyl)benzamide (1.74 g) wasdissolved in 18 ml of tetrahydrofuran, followed by the addition of 0.82ml of triethylamine. Chloroacetyl chloride (0.47 ml) was dropped intothe resulting solution under cooling with ice. The obtained mixture wasstirred at room temperature for 2 hours, followed by the addition ofwater. The precipitates formed were recovered by filtration and washedwith water and ether to give 1.77 g of the title compound as a slightlycream powder (yield: 82%).

M.P.: 174° to 176° C.

MASS: 401(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.91(3H, s), 4.18(2H, s), 4.54(2H, d, J=5.9Hz), 6.55(1H, m), 6.92(1H, d,J=8.4Hz), 7.22(1H, dd, J=8.4, 2.2Hz), 7.38(1H, d, J=2.2Hz), 7.41(1H, dd,J=8.8, 2.4Hz), 7.44(1H, d, J=2.4Hz), 8.53(1H, d, J=8.8Hz), 11.71(1H, brs)

Preparative Example 30

2-(4-Bromopropionylamino)-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR58##

The title compound was obtained as a slightly orange powder in a similarmanner to that of Preparative Example 21 (yield: 95%).

M.P.: 170° to 171° C.

MASS: 439(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

2.88, 3.00(total 2H, t, J=6.8Hz), 3.69, 3.87(total 2H, t, J=6.8Hz),4.50(2H, d, J=5.5Hz), 5.97(2H, s), 6.49(1H, br m), 6.79(1H, d, J=7.9Hz),6.81(1H, d, J=7.9Hz), 6.83(1H, s), 7.41(1H, d, J=2.4Hz), 7.41(1H, dd,J=9.5, 2.4Hz), 8.57(1H, d, J=9.8Hz), 11.12(1H, br s)

Preparative Example 31

2-(4-Bromobutyrylamino)-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR59##

The title compound was obtained as a slightly ocherous powder in asimilar manner to that of Preparative Example 21 (yield: 90%).

M.P.: 158° to 159° C.

MASS: 455(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

2.28(2H, tt, J=7.1, 6.4Hz), 2.61(2H, t, J=7.1Hz), 3.52(2H, t, J=6.4Hz),4.51(2H, d, J=5.5Hz), 5.98(2H, s), 6.46(1H, m), 6.78-6.86(3H, m),7.40(1H, d, J=2.4Hz), 7.40(1H, dd, J=9.5, 2.4Hz), 8.56(1H, d, J=9.5Hz),11.02(1H, br s)

Preparative Example 32

Ethyl trans-4- (tert-butoxycarbonyl)amino!-cyclohexanecarboxylate##STR60##

Monoethyl ester of trans-1,4-cyclohexanedicarboxylic acid (10.00 g) wasdissolved in 200 ml of tert-butanol, followed by the addition of 7.67 mlof triethylamine and 11.85 ml of diphenylphosphoryl azide. The obtainedmixture was heated under reflux for 7 hours and concentrated, followedby the addition of water. The resulting mixture was extracted with ethylacetate. The organic phase was washed with 1N hydrochloric acid, water,1N sodium hydroxide, and a saturated aqueous solution of common salt,dried over anhydrous magnesium sulfate, and concentrated in a vacuum.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (8:1 to 4:1)) to give 5.36 g of the titlecompound as a white solid (yield: 40%).

M.P.: 89° to 91° C.

MASS: 270((M-H)⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.11(2H, m), 1.25(3H, t, J=7.1Hz), 1.44(9H, s), 1.52(2H, m),1.96-2.15(4H, m), 2.20(1H, dt, J=12.3, 3.5Hz), 3.41(1H, br s), 4.11(2H,q, J=7.1Hz), 4.39(1H, br s)

Preparative Example 33

Ethyl trans-4-N-(5-bromobutyl)-N-(tert.-butoxycarbonyl)amino!cyclohexanecarboxylate##STR61##

Ethyl trans-4- (tert.-butoxycarbonyl)amino!-cyclohexanecarboxylate (5.36g) and 1,5-dibromobutane (13.5 ml) were dissolved in 50 ml ofN,N-dimethylformamide, followed by the addition of 0.87 g of 60% sodiumhydride. The obtained mixture was stirred at 50° C. for 5 hours andpoured onto ice-water. The resulting mixture was extracted with ethylacetate. The organic phase was washed with 1N hydrochloric acid, water,a saturated aqueous solution of sodium hydrogencarbonate, water, and asaturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate (10:1 to 5:1)) to give 4.32 g of the title compound as acolorless oil (yield: 52%).

MASS: 420(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.25(3H, t, J=7.1Hz), 1.35-1.60(17H, m), 1.99-2.12(2H, m), 2.19(1H, m),3.05(2H, br s), 3.41(2H, t, J=6.8Hz), 3.86(1H, br s), 4.12(2H, q,J=7.1Hz)

Preparative Example 34

Ethyl trans-4-piperidinocyclohexanecarboxylate ##STR62##

Ethyl trans-4-N-(5-bromobutyl)-N-(tert.-butoxycarbonyl)amino!cyclohexanecarboxylate(5.92 g) was dissolved in 20 ml of chloroform, followed by the additionof 18 ml of 4N hydrochloric acid/ethyl acetate. The obtained mixture wasstirred at room temperature for 14 hours and concentrated. The obtainedresidue was dissolved in 30 ml of ethanol, followed by the addition of5.85 g of anhydrous potassium carbonate. The obtained mixture wasstirred at room temperature for 3 hours, then at 80° C. for 6 hours,followed by the addition of Celite. The resulting mixture was freed frominsolubles by filtration and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia (1000:100:2)) togive 1.91 g of the title compound as a pale-yellow oil (yield: 57%).

MASS: 240(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.25(3H, t, J=7.1Hz), 1.28(2H, m), 1.38-1.51(4H, m), 1.54-1.62(4H, m),1.95(2H, m), 2.04(2H, m), 2.15-2.31(2H, m), 2.48-2.53(4H, m), 4.11(2H,.q, J=7.1Hz)

Preparative Example 35

trans-4-Piperidinocyclohexanecarboxylic acid ##STR63##

Ethyl trans-4-piperidinocyclohexanecarboxylate (1.91 g) was dissolved in20 ml of ethanol. The obtained solution was stirred at room temperaturefor 3 days, adjusted to pH7 with 1N hydrochloric acid, concentrated in avacuum, and purified with an ODS column (solvent: water), followed bythe addition of water. The resulting mixture was freed from insolublesby filtration and concentrated in a vacuum, followed by the addition ofmethanol. The obtained mixture was freed from insolubles by filtrationand concentrated in a vacuum. The obtained solid was washed with etherto give 1.54 g of the title compound as a slightly yellow powder (yield:91%).

MASS: 212(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

1.14-1.32(4H, m), 1.36(2H, m), 1.41-1.49(4H, m), 1.73(2H, m), 1.88(2H,m), 1.96(1H, m), 2.19(1H, m), 2.36-2.48(4H, m)

Preparative Example 36

N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1-pyrazolyl)benzamide ##STR64##

2-Nitro-5-(1-pyrazolyl)benzoic acid (1.40 g), piperonylamine (0.82 ml),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.27 g),1-hydroxybenzotriazole (0.89 g) and triethylamine (0.92 ml) were addedto 20 ml of N,N-dimethylformamide. The obtained mixture was stirred atroom temperature for 14 hours, followed by the addition of water. Theprecipitates formed were recovered by filtration to give 2.19 g of thetitle compound as a slightly yellow powder (Yield: 100%).

M.P.: 179° to 180° C.

MASS: 367(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.56(2H, d, J=5.5 Hz), 5.95(2H, s), 6.18(1H, m), 6.56(1H, dd, J=2.6, 1.8Hz), 6.78(1H, d, J=7.9 Hz), 6.85(1H, dd, J=7.9, 1.6Hz), 6.91(1H, d,J=1.6 Hz), 7.78(1H, d, J=1.8 Hz), 7.83(1H, dd, J=9.0, 2.4 Hz), 7.86(1H,d, J=2.4 Hz), 8.01(1H, d, J=2.6 Hz), 8.19(1H, d, J=9.0 Hz)

Preparative Example 37

N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1,2,4-triazol-1-yl)benzamide##STR65##

The title compound was obtained as a slightly ocherous powder in asimilar manner to that of Preparative Example 28 (yield: 84%).

M.P.: 187° to 190° C.

MASS: 388(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.58(2H, d, J=5.5 Hz), 5.97(2H, s), 6.12(1H, br), 6.76(1H, d, J=7.9 Hz),6.86(1H, dd, J=7.9, 1.7 Hz), 6.91(1H, d, J=1.7 Hz), 7.91(1H, dd, J=9.5,2.6 Hz), 7.91(1H, d, J=2.6 Hz), 8.18(1H, s), 8.27(1H, d, J=9.5 Hz),8.69(1H, s)

Preparative Example 38

N-(4-Chloro-3-methoxybenzyl)phthalimide ##STR66##

2-Chloro-5-methylanisole (8.00 g), N-bromo-succinimide (9.55 g) andbensoyl peroxide (0.62 g) were added to 170 ml of carbon tetrachloride.The obtained mixture was heated under reflux for one hour and cooled byallowing to stand. The resulting mixture was freed from insolubles byfiltration and concentrated in a vacuum. The obtained residue wasdissolved in 100 ml of N,N-dimethylformamide, followed by the additionof 10.41 g of potassium phthalimide. The obtained mixture was stirred at50° C. for one hour, followed by the addition of ice-water. Theprecipitates formed were recovered by filtration and washed with waterand ether to give 8.66 g of the title compound as a slightly yellowpowder (yield: 52%).

M.P.: 156° to 159° C.

MASS: 301(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.80(2H, s), 6.98(1H, dd, J=8.1, 1.8 Hz), 7.05(1H, d, J=1.8Hz), 7.29(1H, d,

J=8.1 Hz), 7.69-7.75(2H, m), 7.82-7.88(2H, m)

Preparative Example 39

N- (2-Methoxy-5-pyridyl)methyl!phthalimide ##STR67##

2-Methoxy-5-pyridinemethanol (2.79 g), phthalimide (2.92 g) andtriphenylphosphine (5.71 g) were added to 35 ml of tetrahydrofuran. Theobtained mixture was cooled with ice, followed by the dropwise additionof a solution of 3.43 ml of diethyl azodicarboxylate in 5 ml oftetrahydrofuran. The resulting mixture was stirred under cooling withice for one hour, then at room temperature for 15 hours, and poured ontoice-water. The resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with 1N hydrochloric acid, water, a saturatedaqueous solution of sodium hydrogencarbonate, water, and a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfate,and concentrated in a vacuum, followed by the addition of benzene. Theresulting mixture was freed from insolubles by filtration andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate (3:1)). The obtainedsolid was washed with n-hexane to give 4.07 g of the title compound as awhite powder (yield: 77%).

M.P.: 122° to 124° C.

MASS: 269(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.78(2H, s), 6.99(1H, d, J=8.6 Hz), 7.68(1H, dd, J=8.6, 2.6Hz), 7.68-7.74(2H, m), 7.81-7.87(2H, m), 8.27(1H, d, J=2.6 Hz)

Preparative Example 40

N-(3-Formyl-4-methoxybenzyl)phthalimide ##STR68##

N-(4-Methoxybenzyl)phthalimide (14.00 g) was dissolved in 100 ml oftrifluoroacetic acid, followed by the addition of 8.09 g ofhexamethylenetetramine in portions. The resulting mixture was stirred atroom temperature for one hour and heated under reflux for 3.5 hours,followed by the addition of ice-water. The obtained mixture wasextracted with ethyl acetate. The organic phase was washed with 1Nsodium hydroxide to give insolubles, which were recovered by filtration.The organic phase was washed with water and a saturated aqueous solutionof common salt, dried over anhydrous magnesium sulfate, andvacuum-distilled to remove the solvent. The obtained solid and the aboveinsolubles were combined and washed with ethyl acetate to give 13.13 gof the title compound as a slightly yellow powder (yield: 85%).

M.P.: 177° to 179° C.

MASS: 296 (MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.82(2H, s), 6.95(1H, d, J=8.6 Hz), 7.64(1H, dd, J=8.6, 2.4Hz), 7.69-7.74(2H, m), 7.82-7.87(3H, m), 10.41(1H, s)

Preparative Example 41

N-(3-Hydroxyimino-4-methoxybenzyl)phthalimide ##STR69##

N-(3-Formyl-4-methoxybenzyl)phthalimide (12.50 g) was suspended in 200ml of tetrahydrofuran, followed by the addition of 3.24 g ofhydroxylamine hydrochloride, 7.64 g of sodium acetate and 30 ml ofwater. The obtained mixture was stirred at 60° C. for 30 minutes andconcentrated in a vacuum. The precipitates formed were recovered byfiltration and washed with ether to give 11.51 g of the title compoundas a slightly yellow powder (yield: 88%).

M.P.: 214° to 217° C.

MASS: 311(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.25(1H, br s), 3.82(3H, s), 4.79(2H, s), 6.85(1H, d, J=8.6 Hz),7.44(1H, dd, J=8.6, 2.4 Hz), 7.66-7.72(2H, m), 7.78(1H, d, J=2.4 Hz),7.80-7.86(2H, m), 8.42(1H, s)

Preparative Example 42

N-(3-Cyano-4-methoxybenzyl)phthalimide ##STR70##

N-(3-Hydroxyimino-4-methoxybenzyl)phthalimide (11.00 g) was suspended in120 ml of xylene, followed by the addition of 3.68 ml of aceticanhydride. The obtained mixture was heated under reflux for 14 hours andcooled by allowing to stand. The precipitates formed were recovered byfiltration and washed with xylene to give 9.11 g of the title compoundas a white powder (yield: 88%).

M.P.: 205° to 209° C.

MASS: 293(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.78(2H, s), 6.92(1H, m), 7.62-7.66(2H, m), 7.70-7.76(2H,m), 7.83-7.88(2H, m)

Preparative Example 43

4-Chloro-3-methoxybenzylamine hydrochloride ##STR71##

N-(4-Chloro-3-methoxybenzyl)phthalimide (8.40 g) and hydrazinemonohydrate (1.49 ml) were added to 100 ml of ethanol. The obtainedmixture was heated under reflux for 1.5 hours, freed from insolubles byfiltration, and concentrated in a vacuum, followed by the addition of 1Nhydrochloric acid. The resulting mixture was freed from insolubles byfiltration. The aqueous phase was washed with ether, alkalified withconcentrated aqueous ammonia and extracted with ether. The ethereralphase was dried over anhydrous sodium sulfate and concentrated in avacuum. The residue was dissolved in ethyl acetate, followed by theaddition of 4N hydrogen chloride/ethyl acetate. The precipitates formedwere recovered by filtration and washed with ethyl acetate to give 4.83g of the title compound as a white powder (yield: 83%).

M.P.: 237° to 242° C.

MASS: 172(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.88(3H, s), 4.01(2H, s), 7.07(1H, dd, J=8.0, 1.8 Hz), 7.45(1H, d, J=8.0Hz), 7.46(1H, d, J=1.8 Hz), 8.57(3H, br s)

Preparative Example 44

5-Aminomethyl-2-methoxypyridine dihydrochloride ##STR72##

The title compound was obtained as a white powder in a similar manner tothat of Preparative Example 36 (yield: 58%).

M.P.: 165° C. (dec.)

MASS: 139(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.87(3H, s), 3.98(2H, q, J=5.9 Hz), 6.89(1H, d, J=8.4 Hz), 7.94(1H, dd,J=8.4, 2.4 Hz), 8.14(1H, m), 8.29(1H, d, J=2.4 Hz), 8.58(2H, br s)

Preparative Example 45

3-Cyano-4-methoxybenzylamine ##STR73##

N-(3-Cyano-4-methoxybenzyl)phthalimide (8.60 g) and hydrazinemonohydrate (1.71 ml) were dissolved in a solvent mixture comprising 100ml of ethanol and 100 ml of 1,4-dioxane. The obtained solution washeated under reflux for 2 hours, freed from insolubles by filration, andconcentrated in a vacuum, followed by the addition of 1N sodiumhydroxide. The resulting mixture was extracted with chloroform. Theorganic phase was dried over anhydrous potassium carbonate andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (solvent: dichloro-methane/methanol/concentrated aqueousammonia (100:10:1)) to give 4.24 g of the title compound as a slightlyyellow solid (yield: 89%).

MASS: 163(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.40(2H, s), 3.84(2H, s), 3.92(3H, s), 6.94(1H, d, J=8.4 Hz), 7.49-7.54(2H, m)

EXAMPLE 1

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride##STR74## (1) 2-Nitro-5-chlorobenzoic acid (5.0 g) and thionyl chloride(3 ml) were heated together under reflux in 50 ml of benzene for 4hours, cooled and concentrated to give an acid chloride. This acidchloride was added to a solution of 3.2 ml of piperonylamine and 5 ml oftriethylamine in THF to conduct a reaction. The reaction mixture waspost-treated in a conventional manner and recrystallized from ethylacetate to give 5.8 g of5-chloro-N-(3,4-methylenedioxybenzyl)-2-nitrobenzamide.

NMR(CDCl₃ : δ)

4.56(2H, d, J=5.7 Hz), 5.97(2H, s+1H, br.s), 6.80(1H, d, J=7.9 Hz),6.85(1H, dd, J=7.9 Hz, 1.8 Hz), 6.90(1H, d, J=1.8 Hz), 7.50(1H, d, J=2.2Hz), 7.54(1H, dd, J=8.6 Hz, 2.2 Hz), 8.05(1H, d, J=8.6 Hz)

(2) 5-Chloro-N-(3,4-methylenedioxybenzyl)-2-nitrobenzamide (620 mg),acetic acid (1 ml), water (1 ml) and ethanol (20 ml) were mildly heatedtogether under reflux, followed by the addition of 1.0 g of powderediron in portions under stirring. The obtained mixture was refluxed forone hour and filtered under heating to remove brown insolubles. Thefiltrate was concentrated, followed by the addition of ethanol. Theresulting mixture was dissolved by heating. Concentrated hydrochloricacid was added to the obtained solution in portions, by which the brownsolution turned yellow and transparent. This yellow transparent solutionwas seeded to give crystals. The resulting mixture was cooled andfiltered to recover the crystals. The crystals were washed with ethanoland ether and dried to give 520 mg of2-amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide.

M.P.: 225° to 228° C. (dec.)

MASS: 305(M-HCl.H⁺)

NMR(400 MHz, δ, DMSO-d₆)

4.32(2H, d, J=5.6 Hz), 5.07(3H, brs), 5.98(2H, s), 6.78(1H, dd, J=8.0,1.2 Hz), 6.84(1H, d, J=8.0 Hz), 6.85(1H, d, J=8.8 Hz), 6.89(1H, d, J=1.2Hz), 7.23(1H, dd, J=8.8, 2.4 Hz), 7.65(1H, d, J=2.4 Hz), 8.94(1H, t,J=5.6 Hz)

EXAMPLE 2

2-Amino-5-chloro-N-(3,4-methylendioxybenzyl)benzamide ##STR75##

2-Amino-5-chlorobenzoic acid (10.0 g), 3,4-methylenedioxybenzyamine(7.62 ml), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride(11.74 g), N-hydroxybenzotriazole (8.27 g) and triethylamine (8.53 ml)were added to 200 ml of acetonitrile. The obtained mixture was stirredat room temperature for 20 hours and concentrated, followed by theaddition of water. The resulting mixture was extracted with ethylacetate. The organic phase was washed with 1N hydrochloric acid, asaturated aqueous solution of sodium hydrogencarbonate, and a saturatedaqueous solution of common salt successively, dried over anhydrousmagnesium sulfate, and concentrated. The obtained solid was washed withethanol to give 14.13 g of the title compound as a slightly orangepowder (yield: 80%).

M.P.: 142° to 145° C.

(white needle from EtOH)

NMR(400 MHz, δ, CDCl₃)

4.49(d, J=5.7 Hz, 2H), 5.48-5.58(br, 2H), 5.96(s, 2H), 6.22(br, 1H),6.63(d, J=8.8 Hz, 1H), 6.78(d, J=7.9 Hz, 1H), 6.81(dd, J=0.5, 7.9 Hz,1H), 6.84(d, J=0.5 Hz, 1H), 7.15(dd, J=2.4, 8.8 Hz, 1H), 7.26(d, J=2.4Hz, 1H)

EXAMPLE 3

2-Amino-5-bromo-N-(3,4-methylenedioxybenzyl)benzamide ##STR76##

A pale-cream needle was obtained (yield: 92%).

M.P.: 157° to 158° C.

(palely orangish-yellow needle from EtOH)

NMR(400 MHz, δ, CDCl₃)

4.49(d, J=5.7 Hz, 2H), 5.57(br, 2H), 5.97(s, 2H), 6.20(br, 1H), 6.58(d,J=8.8 Hz, 1H), 6.78(dd, J=0.7, 7.9 Hz, 1H), 6.81(dd, J=1.3, 7.9 Hz, 1H),6.84(dd, J=0.7, 1.3 Hz, 1H), 7.27(dd, J=2.2, 8.8 Hz, 1H), 7.39(d, J=2.2Hz, 1H)

EXAMPLE 4

2-Amino-5-chloro-N-methyl-N-(3,4-methylenedioxybenzyl)benzamide##STR77##

The title compound was obtained as a pale-yellow powder (yield: 91%).

M.P.: 122° to 124° C.

(slightly yellow needle, aq. EtOH).

NMR(400 MHz, δ, CDCl₃)

2.9(s, 3H), 4.34(s, 2H), 4.55(br, 2H), 5.96(s, 2H), 6.60-6.88(m, 4H),6.66(d, J=8.6 Hz), 6.77(d, J=7.7 Hz), 7.06-7.13(m, 2H)

EXAMPLE 5

2-Amino-5-dimethylaminomethyl-N-(3,4-methylenedioxybenzyl)benzamide##STR78##

Methyl 2-amino-5-((dimethylamino)methyl)benzoate (10.98 g) was dissolvedin 100 ml of ethanol, followed by the addition of 63.1 ml of 1N sodiumhydroxide. The obtained mixture was stirred at room temperature for 14hours, then at 100° C. for 4 hours, followed by the addition of 68.1 mlof 1N hydrochloric acid. The resulting mixture was concentrated to givea pale-yellow powder.

This powder was dissolved in 270 ml of acetonitrile containing 50% ofwater, followed by the addition of 7.19 ml of3,4-methylenedioxybenzylamine, 11.93 g of 1,3-dicyclohexylcarbodiimideand 7.81 g of N-hydroxybenztriazole. The obtained mixture was stirred at70° C. for 14 hours and filtered to remove insolubles. A saturatedaqueous solution of sodium hydrogencarbonate was added to the filtrate,followed by the extraction with chloroform. The organic phase was driedover anhydrous magnesium sulfate and distilled to remove the solvent.The residue was purified by silica gel column chromatography (solvent:dichloromethane/methanol/concentrated aqueous ammonia (1000:100:3)) togive 15.45 g of the title compound as a pale-yellow solid (yield: 90%).

NMR(400 MHz, δ, CDCl₃)

2.26(s, 6H), 3.35(s, 2H), 4.49(d, J=5.9 Hz, 2H), 5.58(br, 2H), 5.95(s,2H), 6.63(d, J=8.4 Hz, 1H), 6.70(br, 1H), 6.77(d, J=7.9 Hz, 1H),6.82(dd, J=1.6, 7.9 Hz, 1H) 6.87(d, J=1.6 Hz, 1H), 7.10(dd, J=1.6, 8.4Hz, 1H), 7.39(d, J=1.6 Hz, 1H)

EXAMPLE 6

Ethyl 1- 4-chloro-2-(3,4-methylenedioxybenzyl)carbamoylphenyl!carbamoyl!piperidine-4-carboxylate ##STR79##

Ethyl 1- (2-carboxy-4-chlorophenyl)carbamoyl!-piperidine-4-carboxylate(850 mg), 3,4-methylenedioxybenzyiamine (0.45 ml),1,3-dicyclohexyl-carbodiimide (0.54 g), N-hydroxybenztriazole (0.36 g)and 4-dimethylaminopyridine (in a catalytic amount) were added to 10 mlof N,N-dimethylformamide. The obtained mixture was stirred at roomtemperature for 16 hours, followed by the addition of water and ethylacetate. The resulting mixture was filtered to remove insolubles,followed by the recovery of the organic phase. The organic phase waswashed with 1N hydrochloric acid, a saturated aqueous solution of sodiumhydrogencarbonate, and a saturated aqueous solution of common salt,dried over anhydrous magnesium sulfate, and distilled to remove thesolvent. The residue was purified by silica gel column chromatography(solvent: dichloromethane/methanol (30:1)) to give 1.10 g of the titlecompound as a white solid (yield: 99%).

M.P.: 153° to 155° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.27(t, J=7.1 Hz, 3H), 1.75(m, 2H), 1.99(m, 2H), 2.52(m, 1H), 3.04(m,2H), 4.08(m, 2H), 4.16(q, J=7.1 Hz, 2H), 4.47(d, J=5.7 Hz), 5.97(s, 2H),6.79(dd, J=0.5, 7.9 Hz, 1H), 6.82(dd, J=1.5, 7.9 Hz, 1H), 6.86(dd,J=0.5, 1.5 Hz, 1H), 7.01(t, J=5.7 Hz, 1H), 7.24(dd, J=2.6, 9.0 Hz, 1H),7.32(d, J=2.6 Hz, 1H), 8.22(d, J=9.0 Hz, 1H), 10.57(s, 1H)

EXAMPLE 7

Ethyl 1-4-chloro-2-(3-chloro-4-methoxybenzyl)carbamoyl!phenyl!carbamoylpiperidine-4-carboxylate##STR80##

A white powder was obtained (yield: 96%).

M.P.: 131° to 132° C. (white needle from aq. EtOH)

NMR(400 MHz, δCDCl₃)

1.27(t, J=7.1 Hz, 3H), 1.75(m, 2H), 1.99(m, 2H), 2.52(m, 1H), 3.05(m,1H), 3.91(s, 3H), 4.08(m, 2H), 4.16(q, J=7.1 Hz, 2H), 4.48(d, J=5.7 Hz,2H), 6.93(d, J=8.4 Hz, 1H), 7.12(t, J=5.7 Hz, 1H), 7.22(dd, J=2.4, 9.0Hz, 1H), 7.22(dd, J=2.2, 8.4 Hz, 1H), 7.32(d, J=2.4 Hz, 1H), 7.40(d,J=2.2 Hz, 1H), 8.19(d, J=9.0 Hz, 1H), 10.54(s, 1H)

EXAMPLE 8

Ethyl 1- 4-chloro-2-(2,3-dihydrobenzofuran-5-yl)methyl!carbamoyl!phenyl!piperidine-4-carboxylate##STR81##

A white powder was obtained (yield: 96%).

M.P.: 120° to 122° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.27(t, J=7.1 Hz, 3H), 1.75(m, 2H), 2.00(m, 2H), 2.52(m, 1H), 3.05(m,2H), 3.22(t, J=8.8 Hz, 2H), 4.10(m, 2H), 4.16(q, J=7.1 Hz, 2H), 4.49(d,J=5.5 Hz, 2H), 4.59(t, J=8.8 Hz, 2H), 6.69(t, J=5.5 Hz, 1H), 6.77(d,J=8.1 Hz, 1H), 7.09(dd, J=1.8, 8.1 Hz, 1H), 7.19(d, J=1.8 Hz, 1H),7.28(dd, J=2.4, 9.2 Hz, 1H), 7.33(d, J=2.4 Hz, 1H), 8.29(d, J=9.2 Hz,1H), 10.68 (s, 1H)

EXAMPLE 9

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(isonicotinoylamino)benzamide##STR82##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.0 g) wasdissolved in 10 ml of pyridine, followed by the addition of 0.64 g ofisonicotinoyl chloride hydrochloride. The obtained mixture was stirredat room temperature for one hour, followed by the addition of ice-water.The resulting mixture was extracted with ethyl acetate. The organicphase was washed with 1N hydrochloric acid, a saturated aqueous solutionof sodium hydrogencarbonate, and a saturated aqueous solution of commonsalt successively, dried over anhydrous magnesium sulfate, and distilledto remove the solvent. The residue was purified by silica gel columnchromatography (solvent: dichloro-methane/methanol (50:1)) andrecrystallized from ethyl acetate to give 630 mg of the title compoundas a white needle (yield: 47%).

M.P.: 204° to 205° C. (EtOAc)

MASS: (FAB)410(MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

61.55 3.94 10.25

found C(%) H(%) N(%)

61.58 3.99 10.16

NMR(400 MHz, δ, DMSO-d₆)

4.44(d, J=5.9 Hz, 2H), 5.99(s, 2H), 6.85(dd, J=1.5, 8.1 Hz, 1H),6.87(dd, J=0.5, 8.1 Hz, 1H), 6.96(dd, J=0.5, 1.5 Hz, 1H), 7.66(dd,J=2.4, 9.0 Hz, 1H), 7.78-7.82(m, 2H), 7.99(d, J=2.4 Hz, 1H), 8.60(d,J=9.0 Hz, 1H), 8.82-8.87(m, 2H), 9.49(t, J=5.9 Hz, 1H), 12.62(s, 1H)

EXAMPLE 10

5-Chloro-2-(nicotinoylamino)-N-(3,4-methylene-dioxybenzyl)benzamide##STR83##

A white needle was obtained (yield: 81%).

M.P.: 152° to 154° C. (ethyl acetate)

MASS: (FAB)410(MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

61.55 3.94 10.25

found C(%) H(%) N(%)

61.42 3.89 10.23

NMR(400 MHz, δ, CDCl₃)

4.54(d, J=5.5 Hz, 2H), 5.96(s, 2H), 6.79(dd, J=0.5, 7.9 Hz, 1H),6.82(br, 1H), 6.82(dd, J=1.6, 7.9 Hz), 6.85(dd, J=0.5, 1.6 Hz, 1H),7.43-7.48(m, 2H), 7.50(d, J=2.4 Hz, 1H), 8.28(ddd, J=1.6, 2.4, 8.1 Hz,1H), 8.75(d, J=8.8 Hz, 1H), 8.78(dd, J=1.6, 4.8 Hz, 1H), 9.26(dd, J=0.4,2.4 Hz, 1H), 12.28(s, 1H)

EXAMPLE 11

5-Chloro-2-chloroacetamido-N-(3,4-methylene-dioxybenzyl)benzamide##STR84##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (5.00 g) wasdissolved in 60 ml of tetrahydrofuran, followed by the addition of 2.52ml of triethylamine. The obtained mixture was stirred under cooling withice. Chloroacetyl chloride (1.44 ml) was dropped into the resultingmixture in such a way that the temperature of the mixture did not exceed10° C. After one hour, ice-water was added to the obtained mixture,followed by the extraction with ethyl acetate. The organic phase waswashed with 1N hydrochloric acid, a saturated aqueous solution of sodiumhydrogencarbonate, and a saturated aqueous solution of common saltsuccessively, dried over anhydrous magnesium sulfate, and distilled toremove the solvent. The obtained solid was washed with a small amount ofethyl acetate to give 5.37 g of the title compound as a slightly yellowpowder (yield: 86%).

M.P.: 186° to 187° C. (white needle from EtOH)

NMR(400 MHz, δ, CDCl₃)

4.18(s, 2H), 4.52(d, J=5.5 Hz, 2H), 5.98(s, 2H), 6.49(br, 1H), 6.79(dd,J=0.5, 7.9 Hz, 1H), 6.82(dd, J=1.6, 7.9 Hz, 1H), 6.85(dd, J=0.5, 1.6 Hz,1H), 7.42(dd, J=2.6, 8.6 Hz, 1H), 7.44(d, J=2.6 Hz, 1H), 8.54(d, J=8.6Hz, 1H), 11.75(br, 1H)

EXAMPLE 12

2-Acetamido-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide ##STR85##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride(100 mg) was reacted with 40 μl of acetyl chloride in 5 ml oftetrahydrofuran in the presence of 150 μl of diisopropylethylamine. Thereaction mixture was subjected to extraction with ethyl acetate andwater and recrystallization from ethyl acetate/hexane to give 85 mg of2-acetamido-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (yield: 84%).

M.P.: 187° to 188° C. (dec.)

MASS: 347(MH⁺)

NMR(400 MHz, δ, CDCl₃)

2.21(3H, s), 4.51(2H, d, J=5.5 Hz), 5.98(2H, s), 6.41(1H, brs), 6.81(2H,s), 6.84(1H, s), 7.38-7.42(2H, m), 8.57(1H, d, J=8.8 Hz), 10.91(1H, brs)

EXAMPLE 13

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylaminobenzamide##STR86##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride(100 mg) was reacted with 50 μl of phenyl chlorocarbonate in 5 ml oftetrahydrofuran in the presence of 150 μl of diisopropylethylamine. Thereaction mixture was subjected to extraction with ethyl acetate andwater and recrystallization from ethyl acetate/hexane to give 110 mg of5-chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylaminobenzamide(yield: 88%).

M.P.: 149° to 150° C.

NMR(400 MHz, δ, CDCl₃)

4.54(2H, d, J=5.6 Hz), 5.98(2H, s), 6.41(1H, brs), 6.80-6.87(3H, m),7.17-7.28(2H, m), 7.37-7.46(5H, m), 8.38(1H, d, J=9.2 Hz), 10.82(1H, s)

EXAMPLE 14

5-Chloro-2-trans-4-(ethoxycarbonyl)cyclohexanecarbonyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR87##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.5 g) wasdissolved in 15 ml of pyridine, followed by cooling with ice. A solutionof 2.28 g of trans-4-(ethoxycarbonyl)cyclohexanecarbonyl chloride in 5ml of dichloromethane was dropped into the solution prepared above insuch a way that the reaction temperature did not exceed 10° C. Theobtained mixture was stirred for 2 hours, followed by the addition ofice-water. The resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with 1N hydrochloric acid, a saturated aqueoussolution of sodium hydrogencarbonate, and a saturated aqueous solutionof common salt successively, dried over anhydrous magnesium sulfate, anddistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (solvent: n-hexane/ethyl acetate (3:1)) andcrystallized from ether to give 1.30 g of the title compound as acolorless prism (yield: 55%).

M.P.: 156° to 158° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.26(t, J=7.1 Hz, 3H), 1.43-1.62(m, 4H), 2.06-2.14(m, 4H), 2.22-2.36(m,2H), 4.13(q, J=7.1 Hz, 2H), 4.50(d, J=5.7 Hz, 2H), 5.97(s, 2H), 6.70(t,J=5.7 Hz, 1H), 6.76-6.85(m, 3H), 7.32(dd, J=2.4, 9.0 Hz, 1H), 7.41(d,J=2.4 Hz, 1H), 8.54(d, J=9.0, 1H), 11.02(s, 1H)

EXAMPLE 15

5-Bromo-2-trans-4-(ethoxycarbonyl)cyclohexane-carbonyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR88##

A white powder was obtained (yield: 79%).

M.P.: 147° to 149° C. (white needle from n-Hex/EtOAc)

NMR(400 MHz, δ, CDCl₃)

1.28(t, J=7.1 Hz, 3H), 1.44-1.53(m, 4H), 2.07-2.15(m, 4H), 2.25-2.37(m,2H), 4.13(q, J=7.1 Hz, 2H), 4.51(d, J=5.7 Hz, 2H), 5.98(s, 2H), 6.51(tlike, J=5 Hz, 1H), 6.78-8.83(m, 2H), 6.84(d, J=0.9 Hz, 1H), 7.53(dd,J=2.4, 8.4 Hz, 1H), 7.55(d, J=2.4 Hz, 1H), 8.53(d, J=8.4 Hz, 1H),11.02(s, 1H)

EXAMPLE 16

5-Chloro-2-3-(ethoxycarbonyl)acryloyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR89##

A slightly yellow needle was obtained (yield: 32%).

M.P.: 181° to 184° C. (ethyl acetate)

MASS: (FAB)431(MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

58.54 4.44 6.50

found C(%) H(%) N(%)

58.44 4.41 6.49

NMR(400 MHz, δ, CDCl₃)

1.35(t, J=7.1 Hz, 3H), 4.28(q, J=7.1 Hz, 2H), 4.52(d, J=5.7 Hz, 2H),5.98(s, 2H), 6.53(m, 1H), 6.78-6.86(m, 3H), 6.90(d, J=15.4 Hz, 1H),7.08(d, J=15.4 Hz, 1H), 7.42-7.48(m, 2H), 8.69(d, J=9.7 Hz, 1H),11.57(s, 1H)

EXAMPLE 17

5-chloro-2-5-(ethoxycarbonyl)valeryl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR90##

A white needle was obtained (yield: 54%).

M.P.: 154° to 158° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.25(t, J=7.1 Hz, 3H), 1.67-1.81(m, 4H), 2.35(t, J=7.3 Hz, 2H), 2.43(t,J=7.0 Hz, 2H), 4.13(q, J=7.1 Hz, 2H), 4.50(d, J=5.7 Hz, 2H), 5.98(s,2H), 6.52(t, J=5.7 Hz), 6.75-6.87(m, 3H), 7.37-7.42(m, 2H), 8.57(d,J=9.3 Hz, 1H), 10.96(s, 1H)

EXAMPLE 18

5-Chloro-2-4-(methoxycarbonyl)benzoyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR91##

A slightly yellow powder was obtained (yield: 73%).

M.P.: 208° to 210° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, DMSO-d₆)

3.90(s, 3H), 4.42(d, J=5.7 Hz, 2H), 5.98(s, 2H), 6.83(dd, J=1.5, 7.9 Hz,1H), 6.86(dd, J=0.5, 7.9 Hz), 6.95(d, J=0.5 Hz, 1H), 7.66(dd, J=2.6, 9.0Hz, 1H), 7.97(d, J=2.6 Hz, 1H), 7.99-8.05(m, 2H), 8.11-8.16(m, 2H),8.61(d, J=9.0 Hz, 1H), 9.47(t, J=5.7 Hz), 12.50(s, 1H)

EXAMPLE 19

5-Chloro-2-(cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR92##

A white needle was obtained (yield: 44%).

M.P.: 141° to 142° C. (Et₂ O)

MASS: (FAB)415(MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

63.69 5.59 6.75

found C(%) H(%) N(%)

63.47 5.60 6.65

NMR(400 MHz, δ, CDCl₃)

1.18-1.39(m, 3H), 1.45-1.57(m, 2H), 1.70(m, 1H), 1.79-1.87(m, 2H),1.95-2.03(m, 2H), 2.29(m, 1H), 4.51(d, J=5.5 Hz, 2H), 6.54(brt, 1H),6.77-6.83(m, 2H), 6.84(m, 1H), 7.37(dd, J=2.2, 8.8 Hz, 1H), 7.40(d,J=2.2 Hz, 1H), 8.58(d, J=8.8 Hz, 1H), 10.91(s, 1H)

EXAMPLE 20

5-Chloro-2-(1-methylpiperidine-4-carbonyl)-amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR93##

A slightly yellow needle was obtained (yield: 13%).

M.P.: 177° to 178° C. (EtOAc)

MASS (FAB)43((MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

61.47 5.63 9.77

found C(%) H(%) N(%)

61.11 5.62 9.70

NMR(400 MHz, δ, CDCl₃)

1.80-1.92(m, 2H), 1.94-2.06(m, 4H), 2.70(m, 1H), 2.29(s, 3H),2.88-2.98(m, 2H), 4.51(d, J=5.7 Hz, 2H), 5.98(s, 2H), 6.52(br, 1H),6.77-6.86(m, 3H), 7.39(dd, J=2.4, 9.7 Hz, 1H), 7.40(d, J=2.4 Hz, 1H),8.60(d, J=9.7 Hz, 1H), 11.05(s, 1H)

EXAMPLE 21

5-Dimethylaminomethyl-2-4-(methoxycarbonyl)benzoyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR94##

A white powder was obtained (yield: 50%).

M.P.: 171° to 174° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

2.24(s, 6H), 3.40(s, 2H), 3.96(s, 3H), 4.54(d, J=5.7 Hz, 2H), 5.96(s,2H), 6.79(d, J=7.9 Hz, 1H), 6.83(dd, J=1.5, 7.9 Hz, 1H), 6.87(d, J=1.5Hz, 1H), 6.88(br, 1H), 7.42(dd, J=1.8, 8.4 Hz, 1H), 7.56(d, J=1.8 Hz,1H), 8.08-8.13(m, 2H), 8.15-8.21(m, 2H), 8.76(d, J=8.4 Hz, 1H), 12.36(s,1H)

EXAMPLE 22

5-Dimethylaminomethyl-2-trans-4-(ethoxycarbonyl)cyclohexanecarbonyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR95##

A white powder was obtained (yield: 32%).

M.P.: 144° to 145° C.

NMR(400 MHz, δ, CDCl₃)

1.25(t, J=7.1 Hz, 3H), 1.43-1.64(m, 4H), 2.05-2.13 (m, 4H), 2.20(s, 6H),2.24-2.35(m, 2H), 3.35(s, 2H), 4.12(q, J=7.1 Hz, 2H), 4.50(d, J=5.7 Hz,2H), 5.95(s, 2H), 6.77(dd, J=0.5, 7.9 Hz, 1H), 6.80(dd, J=1.1, 7.9 Hz,1H), 6.84(dd, J=0.5, 1.1 Hz), 6.86(t, J=5.7 Hz, 1H), 7.32(dd, J=1.8, 8.4Hz, 1H), 7.48(d, J=1.8 Hz, 1H), 8.54(d, J=8.4 Hz, 1H), 11.18(s, 1H)

EXAMPLE 23

8-amino-5-bromoisoquinoline-1-one ##STR96##

A white powder was obtained (yield: 82%).

M.P.: 153° to 155° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.27(t, J=7.1 Hz, 3H), 1.41-1.62(m, 4H), 1.96-2.35(m, 6H), 2.88-3.08(br,3H), 4.14(q, J=7.1 Hz, 2H), 4.45, 4.62(br, total 2H), 5.98(brs, 2H),6.45-6.59, 6.71-6.93(br, total 3H), 7.24(brm, 1H), 7.36(dd, J=2.4, 8.8Hz, 1H), 8.13(d, J=8.8 Hz, 1H), 8.80-9.01(br, 1H)

EXAMPLE 24

5-Chloro-2-(4-hydroxypiperidino)acetamido-N-(3,4-methylenedioxybenzyl)benzamide##STR97##

5-Chloro-2-chloroacetamido-N-(3,4-methylenedioxybenzyl)benzamide (570mg) was dissolved in 5 ml of N,N-dimethylfornamide, followed by theaddition of 450 mg of 4-hydroxypiperidine, 620 mg of potassium carbonateand a catalytic amount of tetra(n-butyl)ammonium iodide. The obtainedmixture was stirred at room temperature for one hour, followed by theaddition of water. The resulting mixture was extracted with ethylacetate. The organic phase was washed with water and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, anddistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (solvent: dichloromethane/methanol (30:1)) andrecrystallized from ethyl acetate/n-hexane to give 560 mg of the titlecompound as a white powder (yield: 84%).

M.P.: 149° to 152° C. (ethyl acetate/n-hexane)

MASS: (FAB)446(MH⁺)

Elemental analysis:

calcd. C(%) H(%) N(%)

59.26 5.43 9.42

found C(%) H(%) N(%)

59.28 5.51 9.37

NMR(400 MHz, δ, DMSO-d₆)

1.55-1.65(m, 2H), 1.68-1.78(m, 2H), 2.19-2.28(m, 2H), 2.64-2.73 (m, 2H),3.06 (s, 2H), 3.50 (m, 1H), 4.39(d, J=5.9 Hz, 2H), 4.58(d, J=3.7 Hz,1H), 5.99(s, 2H), 6.83(dd, J=1.3, 8.1 Hz, 1H), 6.87(d, J=8.1 Hz, 1H),6.92(d, J=1.3 Hz, 1H), 7.54(dd, J=2.6, 9.0 Hz, 1H), 7.73(d, 2.6 Hz, 1H),8.52(d, J=9.0 Hz, 1H), 9.23(t, J=5.9 Hz, 1H), 11.69(s, 1H)

EXAMPLE 25

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(piperidinoacetamido)benzamide##STR98##

A white powder was obtained (yield: 45%).

M.P.: 155° to 156° C. (ethyl acetate/n-hexane)

MASS: (FAB)430(MH⁺)

Elemental analysis:

calcd. (C%) H(%) N(%)

61.47 5.63 9.77

found C(%) H(%) N(%)

61.38 5.61 9.75

NMR(400 MHz, δ, DMSO-d₆)

1.32-1.42(m, 2H), 1.52-1.51(m, 4H), 2.35-2.45(m, 4H), 3.03(s, 2H),4.38(d, J=5.9 Hz, 2H), 5.98(s, 3H), 6.81(dd, J=1.3, 7.9 Hz, 1H), 6.86(d,J=7.9 Hz, 1H), 6.92(d, J=1.3 Hz, 1H), 7.54(dd, J=2.6, 9.0 Hz, 1H),7.74(d, J=2.6 Hz, 1H), 8.54(d, J=9.0 Hz, 1H), 9.25(t, J=5.9 Hz, 1H),11.70(s, 1H)

EXAMPLE 26

5-Chloro-2-4-(ethoxycarbonyl)piperidino!-acetamido-N-(3,4-methylenedioxybenzyl)benzamide##STR99##

A white amorphous substance was obtained (yield: 99%).

NMR(400 MHz, δ, CDCl₃)

1.24(t, J=7.1 Hz, 3H), 1.90-1.98(m, 2H), 1.98-2.10(m, 2H), 2.26-2.36(m,3H), 2.81-2.90(m, 2H), 3.10(s, 2H), 4.13(q, J=7.1 Hz, 2H), 4.50(d, J=5.9Hz, 2H), 5.96(s, 2H), 6.71(t, J=5.9 Hz, 1H), 6.77(dd, J=0.4, 7.9 Hz,1H), 6.81(dd, J=1.8, 7.9 Hz, 1H), 6.85(dd, J=0.4, 1.8 Hz, 1H), 7.30(dd,J=2.4, 9.0 Hz, 1H), 7.40(d, J=2.4 Hz, 1H), 8.49(d, J=9.0 Hz, 1H),11.61(s, 1H)

EXAMPLE 27

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(4-methylpiperazino)acetamido!benzamide ##STR100##

A white powder was obtained (yield: 70%).

M.P.: 162° to 164° C. (EtOAc/n-Hex)

MASS: (FAB)445(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.39         5.66    12.59                                          found    58.80         5.66    12.45                                          ______________________________________                                    

NMR(400 MHz, δ, CDCl₃)

2.35(s, 3H), 2.50-2.75(m, 8H), 3.17(s, 2H), 4.53(d, J=5.7 Hz, 2H),5.97(s, 2H), 6.40(br, 1H), 6.77-6.82(m, 2H), 6.85(m, 1H), 7.39(dd,J=2.0, 8.8 Hz, 1H), 7.41(d, J=2.0 Hz, 1H), 8.57(d, J=8.8 Hz, 1H), 11.56(br, 1H)

EXAMPLE 28

5-chloro-N-(3,4-methylenedioxybenzyl)-2-(3-oxopiperazino)acetamido!benzamide ##STR101##

A white flake was obtained (yield: 52%).

M.P.: 202° to 203° C. (aq. EtOH)

MASS: (FAB)445(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   56.70         4.76    12.59                                          found    56.6580       4.78    12.56                                          ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

2.65(t, J=5.3 Hz, 2H), 3.10(s, 2H), 3.21(s, 2H), 3.23-3.30(m, 2H),4.36(d, J=5.7 Hz, 2H), 5.99(s, 2), 6.81(dd, J=1.6, 8.0 Hz, 1H), 6.88(d,J=8.0 Hz, 1H), 6.90(d, J=1.6 Hz, 1H), 7.56(dd, J=2.6, 9.0 Hz, 1H),7.77(d, J=2.6 Hz, 1H), 7.83(brs, 1H), 8.52(d, J=9.0 Hz, 1H), 9.26(t,J=5.7 Hz, 1H) 11.72(s, 1H)

EXAMPLE 29

5-Chloro-2-4-(ethoxycarbonyl)butylamino!-N-(3,4-methylenedioxybenzyl)benzamide##STR102##

6-Chloro-1-4-(ethoxycarbonyl)butyl!-1,2-dihydro-4H-1,3-benzoxazine-2,4-dione (3.50g) was dissolved in 35 ml of N,N-dimethylformamide, followed by theaddition of 0.13 g of 4-dimethylaminopyridine and 1.47 ml of3,4-methylenedioxybenzylamine. The obtained mixture was stirred at roomtemperature for one hour, followed by the addition of ice-water. Theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with 1N hydrochloric acid, a saturated aqueous solution ofsodium hydrogen-carbonate, and a saturated aqueous solution of commonsalt successively, dried over anhydrous magnesium sulfate, and distilledto remove the solvent. The obtained solid was washed with ethanol togive 3.35 g of the title compound as a slightly yellow powder (yield:72%).

M.P.: 89° to 91° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

1.25(t, J=7.1 Hz, 3H), 1.65-1.80(m, 4H), 2.35(t, J=7.0 Hz, 2H), 3.13(m,2H), 4.13(q, J=7.1 Hz, 2H), 4.46(d, J=5.7 Hz, 2H), 5.96(s, 2H),6.26(brt, 1H), 6.60(d, J=9.0 Hz, 1H), 6.76-6.81(m, 2H), 6.83(m, 1H),7.22(dd, J=2.4, 9.0 Hz, 1H), 7.26(d, J=2.4 Hz, 1H), 7.52(brt, 1H)

EXAMPLE 30

5-Chloro-2-3-(thoxycarbonyl)propylamino!-N-(3,4-methylenedioxybenzyl)benzamide##STR103##

A pale-yellow solid was obtained (yield: 88%).

NMR(400 MHz, δ, CDCl₃)

1.26(t, J=7.1 Hz, 3H), 1.97(m, 2H), 2.42(t, J=7.3 Hz, 2H), 3.19(m, 2H),4.14(q, J=7.1 Hz, 2H), 4.47(d, J=5.5 Hz, 2H), 5.96(s, 2H), 6.26(m, 1H),6.64(d, J=8.8 Hz, 1H), 6.76-6.82(m, 2H), 6.83(m, 1H), 7.22(dd, J=2.4,8.8 Hz, 1H), 7.27(d, J=2.4 Hz, 1H), 7.57(m, 1H)

EXAMPLE 31

5-Chloro-2-methylamino-N-(3,4-methylenedioxybenzyl)benzamide ##STR104##

A slightly gray powder was obtained (yield: 94%).

M.P.: 152° to 154° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, DMSO-d₆)

2.76(d, J=5.1 Hz, 3H), 4.31(d, J=5.9 Hz, 2H), 5.98(s, 2H), 6.64(d, J=9.0Hz, 1H), 6.73(dd, J=1.5, 7.9 Hz, 1H), 6.85(d, J=7.9 Hz, 1H), 6.88(d,J=1.5 Hz, 1H), 7.31(dd, J=2.6, 9.0 Hz, 1H), 7.64(d, J=2.6 Hz, 1H),7.74(q, J=5.1 Hz, 1H), 8.93(t, J=5.9 Hz, 1H)

EXAMPLE 32

5-Chloro-2-4-(methoxycarbonyl)benzyl!-N-(3,4-methylenedioxybenzyl)benzamid##STR105##

A slightly yellow powder was obtained (yield: 89%).

M.P.: 156° to 158° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

3.91(s, 3H), 4.46(d, J=5.5 Hz, 2H), 4.50(d, J=5.5 Hz, 2H), 5.97(s, 2H),6.29(brt, J=5 Hz, 1H, 6.46(d, J=9.0 Hz, 1H), 6.79(dd, J=0.7, 7.9 Hz,1H), 6.82(dd, J=1.5, 7.9 Hz), 6.85(dd, J=0.7, 1.5 Hz), 7.14(dd, J=2.6,9.0 Hz), 7.31(d, J=2.6 Hz, 1H), 7.38-7.43(m, 2H), 7.97-8.02(m, 2H),8.16(brt, J=5 Hz, 1H)

EXAMPLE 33

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(4-picolyl)aminobenzamide##STR106##

A suspension of 60% sodium hydride in mineral oil (1.34 g) was suspendedin 50 ml of N,N-dimethyl-acetamide, followed by the addition of 3.0 g of6-chloro-1,2-dihydro-4H-1,3-benzoxazine in portions. The obtainedmixture was stirred at room temperature for one hour, followed by theaddition of 4-picolyl chloride hydrochloride in portions. After 1.5hours, the resulting mixture was heated to 50° C., stirred for 24 hoursand cooled by allowing to stand. 3,4-Methylenedioxybenzylamine (2.1 ml)and 4-dimethylaminopyridine (0.19 g) were added to the mixture. Theobtained mixture was stirred at room temperature for one hour, followedby the addition of ice-water. The resulting mixture was extracted withethyl acetate. The organic phase was washed with water and a saturatedaqueous solution of common salt, dried over anhydrous magnesium sulfate,and distilled to remove the solvent. The residue was purified by silicagel column chromatography (solvent: n-hexane/ethyl acetate (1:1 to 1:2))and recrystallized from ethanol to give 870 mg of the title compound asa white needle (yield: 14%).

M.P.: 163° to 166° C.

MASS: (FAB)396(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   63.72         4.58    10.62                                          found    63.79         4.57    10.62                                          ______________________________________                                    

NMR(400 MHz, δ, CDCl₃)

4.43(d, J=5.9 Hz, 2H), 4.51(d, J=5.7 Hz, 2H), 5.97(s, 2H), 6.40(m, 1H),6.40(d, J=9.0 Hz, 1H), 6.79(dd, J=0.5, 7.9 Hz, 1H), 6.82(dd, J=1.5, 7.9Hz, 1H), 6.85(dd, J=0.5, 1.5 Hz, 1H), 7.15(dd, J=2.4, 9.0 Hz, 1H),7.24-7.27(m, 2H), 7.33(d, J=2.4 Hz, 1H), 8.21(t, J=5.9 Hz, 1H),8.52-8.55(m, 2H)

EXAMPLE 34

5-Chloro-2-trans-4-(ethoxycarbonyl)cyclohexyl!methyl!amino-N-(3,4-methylenedioxybenzyl)benzamide##STR107##

A pale-yellow powder was obtained (yield: 11%).

M.P.: 128° to 129° C.

(pale-yellow needle from aq. EtOH)

NMR(400 MHz, δ, CDCl₃)

0.9-1.11(m, 2H), 1.25(t, J=7.1 Hz, 3H), 1.38-1.51(m, 2H), 1.63(m, 1H),1.90-1.99(m, 2H), 1.99-2.06(m, 2H), 2.25(m, 1H), 2.95-3.02(m, 2H),4.12(q, J=7.1 Hz, 2H), 4.48(q, J=5.7 Hz, 2H), 5.96(s, 2H), 6.21(brt,1H), 6.60(d, J=9.0 Hz, 1H), 6.76-6.82(m, 2H), 6.83(m, 1H), 7.21(dd,J=2.6, 9.0 Hz, 1H), 7.26(d, J=2.6 Hz, 1H), 7.65(br, t, 1H)

EXAMPLE 35

2-(4-Carboxybutyryl)amino!-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR108##

2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (1.0 g) wasdissolved in 10 ml of pyridine, followed by the addition of 0.41 g ofglutaric anhydride. The obtained mixture was stirred at room temperaturefor 20 hours and concentrated, followed by the addition of ethylacetate. The resulting mixture was extracted with 1N sodium hydroxide.The pH of the aqueous phase was adjusted to about 2. The precipitatesformed were recovered by filtration and recrystallized from aqueousethanol to give 500 mg of the title compound as a white powder (yield:36%).

M.P.: 154° to 155° C. (aq. EtOH)

MASS: (FAB)419(NH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.35         4.57    6.69                                           found    57.17         4.56    6.64                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.80(dt, J=7.3, 7.5 Hz, 2H), 2.28(t, J=7.3 Hz, 2H), 2.38(t, 7.5 Hz, 2H),4.37(d, J=5.9 Hz, 2H), 5.99(s, 2H), 6.82(dd, J=1.6, 7.9 Hz, 1H),6.87(dd, J=0.4, 7.9 Hz, 1H), 6.93(dd, J=0.4, 1.6 Hz, 1H), 7.55(dd,J=2.6, 9.0 Hz, 1H), 7.82(d, J=2.6 Hz, 1H), 8.38(d, J=9.0 Hz, 1H),9.30(t, J=5.9 Hz, 1H), 11.17(s, 1H)

EXAMPLE 36

2-(3-Carboxypropionyl)amino!-5-chloro-N-(3,4-methylenedioxybenzyl)benzamid##STR109##

A white needle was obtained (yield: 38%).

M.P.: 217° to 220° C. (EtOH)

MASS: (FAB)405(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   56.37         4.23    6.92                                           found    56.24         4.25    6.88                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

2.48-2.60(m, 4H), 4.38(d, J=5.9 Hz, 2H), 5.99(s, 2H), 6.82(ddd, J=0.4,1.7, 7.9 Hz, 1H), 6.87(dd, J=1.7, 7.9 Hz, 1H), 6.93(dd, J=0.4, 1.7 Hz,1H), 7.55(dd, J=2.4, 9.0 Hz, 1H), 7.83(d, J=2.4 Hz, 1H), 8.38(d, J=9.0Hz, 1H), 9.31(t, J=5.9 Hz, 1H), 11.24(s, 1H)

EXAMPLE 37

2-N-(4-Carboxybutyryl)-N-methyl!amino-5-chloro-N'-(3,4-methylenedioxybenzyl)benzamide##STR110##

A white amorphous substance was obtained (yield: 39%).

MASS: (FAB)433(MH⁺)

NMR(400 MHz, δ, CDCl₃)

1.75-1.86(m, 2H), 1.99-2.48(m, 4H), 3.15, 3.22(s, total 3H), 4.41(dd,J=5.7, 14.5 Hz, 1H), 4.46(dd, J=5.7, 14.5 Hz, 1H), 5.94(s, 2H), 6.69,7.04(m, total 1H), 6.73-6.82(m, 3H), 7.05, 7.12(d, J=8.4 Hz, total 1H),7.40, 7.44(dd, J=2.4, 8.4 Hz, 1H), 7.47, 7.60(d, J=2.4 Hz, 1H)

EXAMPLE 38

1- 4-Chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylicacid ##STR111##

Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N sodium hydroxide (65ml) were added to 10.09 g of ethyl 1- 4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylate.The obtained mixture was stirred at room temperature for 2 hours,followed by the addition of 100 ml of water. The resulting mixture wasconcentrated, followed by the addition of water and ethyl acetate. Theaqueous phase formed was recovered and the organic phase was extractedwith 1N sodium hydroxide. The aqueous phase thus formed and the aboveaqueous phase were combined and adjusted to about pH 2 with concentratedhydrochloric acid. The precipitates formed were recovered by filtrationand recrystallized from aqueous ethanol to give 6.84 g of the titlecompound as a white needle (yield: 72%).

M.P.: 263° to 264° C. (EtOH)

MASS: (FAB)460(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.46         4.82    9.14                                           found    57.39         4.73    9.09                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.46(m, 2H), 1.86(m, 2H), 2.49(m, 1H), 2.98(m, 2H), 3.91(m, 2H), 4.38(d,J=5.7 Hz, 2H), 5.98(s, 2H), 6.81(dd, J=1.5, 8.1 Hz, 1H), 6.86(d, J=8.1Hz, 1H), 6.91(d, J=1.5 Hz, 1H), 7.49(dd, J=2.6, 9.0 Hz, 1H), 7.82(d,J=2.6 Hz, 1H), 8.31(d, J=9.0 Hz, 1H), 9.35(t, J=5.7 Hz), 11.06(s, 1H)

EXAMPLE 39

2-(trans-4-Carboxycyclohexanecarbonyl)amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR112##

Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N sodium hydroxide (65ml) were added to 10.0 g of 5-chloro-2-trans-4-(ethoxycarbonyl)cyclohexanecarbonyl!amino-N-(3,4-methylenedioxybenzyl)benzamide.The obtained mixture was stirred at room temperature for 8 hours andconcentrated. The residue was dissolved in water and subjected toreversed phase silica gel chromatography (solvent: water to methanolcontaining 30% of water). The fractions were combined and concentratedto remove the methanol. The resulting solution was acidified with 1Nhydrochloric acid. The precipitates formed were recovered by filtrationand recrystallized from aqueous ethanol to give 7.10 g of the titlecompound as a white needle (yield: 75%).

M.P.: 228° to 230° C. (EtOH)

MASS: (FAB)459(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   60.20         5.05    6.10                                           found    59.95         5.11    6.08                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.31-1.48(m, 4H), 1.87-2.03(m, 4H), 2.13-2.29(m, 2H), 4.38(d, J=5.7 Hz,2H), 5.99(s, 2H), 6.82(dd, J=1.6, 7.9 Hz, 1H), 6.87(d, J=7.9 Hz, 1H),6.93(d, J=1.6 Hz, 1H), 7.54(dd, J=2.6, 9.0 Hz, 1H), 7.83(d, J=2.6 Hz,1H), 8.40(d, J=9.0 Hz,1H), 9.32(t, J=5.7 Hz, 1H), 11.19(s, 1H)

EXAMPLE 40

2-(5-Carboxyvaleryl)amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR113##

A white needle was obtained (yield: 30%).

M.P.: 197° to 199° C. (EtOH)

MASS: (FAB)433(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   58.27         4.89    6.47                                           found    58.03         4.96    6.38                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.49-1.63(m, 4H), 2.23(t, J=7.3 Hz, 2H), 2.34(t, J=6.8 Hz, 2H), 4.37(d,5.7 Hz, 2H), 5.99(s, 2H), 6.82(dd, J=1.6, 7.9 Hz, 1H). 6.87(dd, J=0.4,7.9 Hz, 1H), 6.93(dd, J=0.4, 1.6 Hz, 1H), 7.55(dd, J=2.6, 9.0 Hz, 1H),7.82(d, J=2.6 Hz, 1H), 8.39(d, J=9.0 Hz, 1H), 9.30(t, J=5.7 Hz, 1H),11.15(s, 1H)

EXAMPLE 41

2-(4-Carboxybenzoyl)amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR114##

A white needle was obtained (yield: 74%).

M.P.: 260° to 262° C. (aq. EtOH)

MASS: (FAB)453(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   61.00         3.78    6.19                                           found    60.83         3.98    6.09                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

4.42(d, J=5.7 Hz, 2H), 5.98(s, 2H), 6.83(dd, J=1.5, 7.9 Hz, 1H),6.86(dd, J=0.5, 7.9 Hz, 1H), 6.95(dd, J=0.5, 1.5 Hz, 1H), 7.66(dd,J=2.4, 9.0 Hz, 1H), 7.97(d, J=2.4 Hz, 1H), 7.98-8.03(m, 2H).8.09-8.15(m, 2H), 8.62(d, J=9.0 Hz, 1H), 9.47(t, J=5.7 Hz, 1H), 12.50(s,1H)

EXAMPLE 42

1- 4-chloro-2-(2,3-dihydrobenzofuran-5-yl)methyl!carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylicacid ##STR115##

A white needle was obtained (yield: 26%).

M.P.: 258° to 259° C. (aq. EtOH)

MASS: (FAB)458(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   60.33         5.28    9.18                                           found    60.18         5.25    9.16                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.47(m, 2H), 1.86(m, 2H), 2.47(m, 1H), 2.99(m, 2H), 3.15(t, J=8.8 Hz,2H), 3.91(m, 2H), 4.38(d, J=5.9 Hz, 2H), 4.50(t, J=8.8 Hz, 2H), 6.70(d,J=8.2 Hz, 1H), 7.05(dd, J=1.8, 8.2 Hz, 1H), 7.20(d, J=1.8 Hz, 1H),7.48(dd, J=2.6, 9.2 Hz, 1H), 7.82(d, J=2.6 Hz, 1H), 8.32(d, J=9.2 Hz,1H), 9.34(t, J=5.9 Hz, 1H), 11.12(s, 1H)

EXAMPLE 43

1-4-Chloro-2-(3-chloro-4-methoxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylicacid ##STR116##

A white needle was obtained (yield: 63%).

M.P.: 288° to 291° C. (aq. EtOH)

MASS: (FAB)480(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   55.01         4.83    8.75                                           found    54.80         4.81    8.64                                           ______________________________________                                    

NMR(400 MHz, δ, DMSO-d₆)

1.47(m, 2H), 1.86(m, 2H), 2.46(m, 1H), 2.99(m, 2H), 3.83(s, 3H), 3.91(m,2H), 4.40(d, J=5.7 Hz, 2H), 7.11(d, J=8.6 Hz, 1H), 7.28(dd, J=2.0, 8.6Hz, 1H), 7.40(d, J=2.0 Hz, 1H), 7.49(dd, J=2.6, 9.0 Hz, 1H), 7.82(d,J=2.6 Hz, 1H), 8.31(d, J=9.0 Hz, 1H), 9.37(t, J=5.7 Hz), 11.02(s, 1H)

EXAMPLE 44

2-(3-Carboxyacryoyl)amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide##STR117##

A white needle was obtained (yield: 9%)

M.P.: 256° to 258° C. (dec.) (ethanol)

MASS: (FAB)403(MH⁺)

Elemental analysis:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   56.66         3.75    6.95                                           found    56.17         3.68    6.75                                           ______________________________________                                    

NMR(400 MHz, δ , DMSO-d₆)

4.38(d, J=5.7 Hz, 2H), 5.98(s, 2H), 6.64(d, J=15.4 Hz, 1H), 6.82(dd,J=1.5, 7.9 Hz, 1H), 6.86(d, J=7.9 Hz, 1H), 6.93(d, J=1.5 Hz, 1H),7.00(d, J=15.4 Hz, 1H), 7.60(dd, J=2.4, 8.8 Hz, 1H), 7.83(d, J=2.4 Hz,1H), 8.29(d, J=8.8 Hz, 1H), 9.29(t, J=5.7 Hz, 1H), 11.49(s, 1H)

EXAMPLE 45

5-Bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino-N-(3,4-methylenedioxybenzyl)benzamide##STR118##

A white needle was obtained (yield: 74%).

M.P.: 236° to 238° C. (white needle from aq. EtOH)

NMR(400 MHz, δ, DMSO-d₆)

1.31-1.47(m, 4H), 1.85-2.03(m, 4H), 2.14-2.30(m, 2H), 4.38(d, J=5.9 Hz,2H), 5.99(s, 2H), 6.81(dd, J=1.5, 7.9 Hz, 1H), 6.87(d, J=7.9 Hz, 1H),6.93(d, J=1.5 Hz, 1H), 7.67(dd, J=2.4, 9.0 Hz, 1H), 7.94(d, J=2.4 Hz,1H), 8.35(d, J=9.0 Hz, 1H), 9.33(t, J=5.9 Hz, 1H), 11.20(s, 1H),12.09(br, 1H)

EXAMPLE 46

2-(trans-4-Carboxycyclohexanecarbonyl)amino-5-chloro-N-methyl-N-(3,4-methylenedioxybenzyl)benzamide##STR119##

A white prism was obtained (yield: 78%).

M.P.: 202° to 204° C. (white prism from aq. EtOH)

NMR(400 MHz, δ, DMSO-d₆)

1.24-1.50(m, 4H), 1.66-2.01(m, 4H), 2.10-2.42(m, 2H), 2.67, 2.83(s,total 3H), 4.22, 4.51(s, total 2H), 6.00, 6.01(s, total 2H), 6.62-6.67,6.80-6.89(m, total 2H), 6.77, 7.02(s, total 1H), 7.35-7.57(m, 3H), 9.57,9.62(s, total 1H), 12.08(br, 1H)

EXAMPLE 47

Sodium trans-4-4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!aminomethylcyclohexanecarboxylate##STR120##

Ethanol (7 ml), tetrahydrofuran (7 ml) and 1N sodium hydroxide (7 ml)were added to 800 mg of 5-chloro-2-trans-4-(ethoxycarbonyl)cyclohexyl!-methyl!amino-N-(3,4-methylenedioxybenzyl)benzamide.The obtained mixture was stirred at room temperature for 17 hours.

The reaction mixture was concentrated and purified by reversed phasesilica gel column chromatography (solvent: water to 40% methanol). Thefractions were combined and concentrated to dryness. The solid waswashed with 2-propanol to give 780 mg of the title compound as aslightly yellow powder (yield: 98%).

M.P.: 266° to 271° C. (dec.)

MASS: (FAB)489((M+Na)⁺), 467(MH⁺)

NMR(400 MHz, δ, DMSO-d₆)

0.85-1.00(m, 2H), 1.13-1.28(m, 2H), 1.44(m, 1H), 1.69-1.80(m, 2H),1.80-1.92(m, 2H), 2.85-2.97(m, 2H), 4.32(d, J=5.5 Hz, 2H), 5.98(s, 2H),6.67(d, J=9.3 Hz, 1H), 6.78(dd, J=1.5, 7.8 Hz, 1H), 6.85(d, J=7.8 Hz,1H), 6.88(d, J=1.5 Hz, 1H), 7.26(dd, J=2.4, 9.3 Hz, 1H), 7.66(d, J=2.4Hz, 1H), 7.97(t, J=5.5 Hz, 1H), 9.03(t, J=5.7 Hz, 1H)

EXAMPLE 48

Sodium 4-4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!aminomethylbenzoate##STR121##

A slightly yellow powder was obtained (yield: 88%).

M.P: >300° C.

MASS: (FAB)461(MH⁺), 483((M+Na)⁺)

NMR(400 MHz, δ, DMSO-d₆)

4.33(d, J=5.7 Hz, 2H), 4.36(d, J=5.5 Hz, 2H), 5.99(s, 2H), 6.63(d, J=9.0Hz, 1H), 6.80(dd, J=1.5, 7.9 Hz, 1H), 6.88(d, J=7.9 Hz, 1H), 6.90(d,J=1.5 Hz, 1H), 7.20(d, J=8.1 Hz, 2H), 7.23(dd, J=2.6, 8.1 Hz, 1H),7.67(d, J=2.6 Hz, 1H), 7.81(d, J=8.1 Hz, 2H), 8.29(t, J=5.7 Hz, 1H),9.03(t, J=5.5 Hz, 1H)

EXAMPLE 49

Sodium 4-4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!aminobutyrate##STR122##

A slightly yellow powder was obtained (yield: 35%).

MASS: (FAB)435(MH+Na⁺)

NMR(400 MHz, δ, DMSO-d₆)

1.71(m, 2H), 1.98(m, 2H), 3.06(m, 2H), 4.32(d, J=4.4 Hz, 2H), 5.98(s,2H), 6.72(d, J=9.0 Hz, 1H), 6.79(dd, J=1.1, 7.9 Hz, 1H), 6.85(d, J=7.9Hz, 1H), 6.89(d, J=1.1 Hz, 1H), 7.25(dd, J=2.4, 9.0 Hz, 1H), 7.64(d,J=2.4 Hz, 1H), 7.86(t, J=4.4 Hz, 1H), 9.00(t, J=5.5 Hz)

EXAMPLE 50

Sodium 5-4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!aminovalerate##STR123##

A slightly yellow powder was obtained (yield: 41%).

MASS: (FAB)449((M+Nal)⁺)

NMR(400 MHz, δ, DMSO-d₆)

1.48-1.60(m, 4H), 1.88-1.98(m, 2H), 2.99-3.08(m, 2H), 4.32(d, J=5.3 Hz,2H), 5.97(s, 2H), 6.66(d, J=9.0 Hz, 1H), 6.79(dd, J=1.5, 7.9 Hz, 1H),6.85(d, J=7.9 Hz), 6.89(d, J=1.5 Hz, 1H), 7.27(dd, J=2.4, 9.0 Hz),7.67(d, J=2.4 Hz, 1H), 7.87(t, J=5.3 Hz, 1H), 9.04(t, J=8.3 Hz, 1H)

EXAMPLE 51

Sodium 1-4-chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoylmethyl!piperidine-4-carboxylate##STR124##

A white powder was obtained (yield: 76%).

M.P.: 244° to 249° C. (dec.)

MASS: (FAB)518((M+Na)⁺), 496(MH⁺)

NMR(400 MHz, δ, DMSO-d₆)

1.68-1.85(m, 4H), 2.05-2.16(m, 2H), 2.67-2.77(m, 2H), 3.01(s, 2H),3.42(br, 1H), 4.38(br, s, 2H), 5.98(s, 2H), 6.85(dd, J=1.3, 8.1 Hz, 1H),6.87(dd, J=0.7, 8.1 Hz, 1H), 6.93(d, J=0.7 Hz, 1H), 7.52(dd, J=2.6, 9.0Hz, 1H), 7.74(d, J=2.6 Hz, 1H), 8.48(d, J=9.0 Hz, 1H), 9.38 (br, 1H),11.59 (br, 1H)

EXAMPLE 52

Sodium 4-4-dimethylaminomethyl-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!benzoate##STR125##

A white powder was obtained (yield: 48%).

M.P.: 280° C. (dec.)

NMR(400 MHz, δ, DMSO-d₆)

2.16(s, 6H), 3.38(s, 2H), 4.33(d, J=4.9 Hz, 2H), 5.98(s, 2H),6.82-6.88(m, 2H), 6.95(s, 1H), 7.48(dd, J=0.5, 8.4 Hz, 1H), 7.92(d,J=0.5 Hz, 1H), 7.82(d, J=8.1 Hz, 2H), 7.99(d, J=8.1 Hz, 1H), 8.59(d,J=8.4 Hz, 1H), 9.45(br, 1H), 12.42(s, 1H)

EXAMPLE 53

2-Amino-5-bromo-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide##STR126##

2-Amino-5-bromo-4-methoxybenzoic acid (1.50 g), piperonylamine (0.84ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.29g), 1-hydroxybenztriazole (0.91 g) and triethylamine (0.93 ml) wereadded to 20 ml of N,N-dimethylformamide. The obtained mixture wasstirred at room temperature for 20 hours, followed by the addition ofwater. The precipitates formed were recovered by filtration to give 2.19g of the title compound as a slightly orange powder (yield: 100%).

M.P.: 143° to 144° C.

MASS: 378(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.85(3H, s), 4.46(2H, d, J=5.7 Hz), 5.81(2H, s), 5.95(2H, s), 6.15(1H,s), 6.15(1H, m), 6.77(1H, dd, J=7.9, 0.5 Hz), 6.79(1H, dd, J=7.9, 2.2Hz), 6.83(1H, dd, J=2.2, 0.5 Hz), 7.44(1H, s)

EXAMPLE 54

2-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)-4-methoxybenzamide##STR127##

The title compound was obtained as a slightly orange powder in a similarmanner to that of Example 53 (yield: 100%).

M.P.: 146° to 148° C.

MASS: 400(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.85(3H, s), 3.89(3H, s), 4.47(2H, d, J=5.7 Hz), 5.81(2H, s), 6.15(1H,s), 6.23(1H, t, J=5.7 Hz), 6.89(1H, d, J=8.4 Hz), 7.19(1H, dd, J=8.4,2.2 Hz), 7.34(1H, d, J=2.2 Hz), 7.45(1H, s)

EXAMPLE 55

2-Amino-5-chloro-N-(3-chloro-4-methoxybenzyl)benzamide ##STR128##

The title compound was obtained as a slightly ocherous powder in asimilar manner to that of Example 53 (yield: 93%).

M.P.: 176° to 178° C.

MASS: 324(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.50(2H, d, J=5.7 Hz), 5.54(2H, s), 6.28(1H, s), 6.63(1H,d, J=8.8 Hz), 6.90(1H, d, J=8.4 Hz), 7.15(1H, dd, J=8.4, 2.4 Hz),7.21(1H, dd, J=8.4, 2.2 Hz), 7.27(1H, d, J=2.4 Hz), 7.36(1H, d, J=2.2Hz)

EXAMPLE 56

2-Amino-5-chloro-N- (2-methoxy-5-pyridyl)methyl!benzamide ##STR129##

The title compound was obtained as a white powder in a similar manner tothat of Example 53 (yield: 73%).

M.P.: 156° to 159° C.

MASS: 292(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.94(3H, s), 4.52(2H, d, J=5.7 Hz), 5.54(2H, s), 6.22(1H, s), 6.63(1H,d, J=8.8 Hz), 6.75(1H, d, J=8.4 Hz), 7.15(1H, dd, J=8.8, 2.4 Hz),7.25(1H, dd, J=2.4 Hz), 7.60(1H, dd, J=8.4, 2.6 Hz), 8.14(1H, d, J=2.6Hz)

EXAMPLE 57

2-Amino-N-(3,4-methylenedioxybenzyl)-5-trifluoromethoxybenzamide##STR130##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Example 53 (yield: 100%).

M.P.: 150° to 153° C.

MASS: 354(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.50(2H, d, J=5.7 Hz), 5.59(2H, s), 5.96(2H, s), 6.19(1H, s), 6.66(1H,d, J=8.8 Hz), 6.78(1H, dd, J=7.9, 0.5 Hz), 6.81(1H, dd, J=7.9, 1.5 Hz),6.85(1H, dd, J=1.5, 0.5 Hz), 7.09(1H, m), 7.14(1H, d, J=2.6 Hz)

EXAMPLE 58

2-Amino-5-chloro-N-(3-cyano-4-methoxybenzyl)benzamide ##STR131##

The title compound was obtained as a white powder in a similar manner tothat of Example 53 (yield: 100%).

M.P.: 174° to 177° C.

MASS: 315(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.89(3H, s), 4.36(2H, d, J=5.7 Hz), 6.59(2H, s, 6.73(1H, d, J=8.8 Hz),7.17(1H, dd, J=8.8, 2.6 Hz), 7.22(1H, d, J=8.6 Hz), 7.58-7.66(3H, m),8.89(1H, t, J=5.7 Hz)

EXAMPLE 59

2-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)benzamide ##STR132##

The title compound was obtained as a slightly orange powder in a similarmanner to that of Example 53 (yield: 98%).

M.P.: 168° to 170° C.

MASS: 370(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.49(2H, d, J=5.7 Hz), 5.56(2H, s), 6.30(1H, s), 6.58(1H,d, J=8.8 Hz), 6.90(1H, d, J=8.4 Hz), 7.20(1H, dd, J=8.4, 2.2 Hz),7.27(1H, dd, J=8.8, 2.2 Hz), 7.35(1H, d, J=2.2 Hz), 7.40(1H, d, J=2.2Hz)

EXAMPLE 60

2-Amino-5-chloro-N-(4-chloro-3-methoxybenzyl)benzamide ##STR133##

The title compound was obtained as a slightly ocherous powder in asimilar manner to that of Example 53 (yield: 99%).

M.P.: 162° to 163° C.

MASS: 324 (M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.91(3H, s), 4.55(2H, d, J=5.7 Hz), 5.54(2H, s), 6.31(1H, s), 6.46(1H,d, J=8.8 Hz), 6.87(1H, dd, J=8.1, 1.8 Hz), 6.92(1H, d, J=1.8 Hz),7.16(1H, dd, J=8.8, 2.4 Hz), 7.28(1H, d, J=2.4 Hz), 7.34(1H, d, J=8.1Hz)

EXAMPLE 61

2-Amino-5-cyano-N-(3,4-methylenedioxybenzyl)benzamide ##STR134##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Example 1 (yield: 88%).

M.P.: 163° to 166° C.

MASS: 295(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.49(2H, d, J=5.5 Hz), 5.96(2H, s), 6.22(1H, s), 6.40(1H, m), 6.63(1H,d, J=8.6 Hz), 6.79(1H, d, J=8.1 Hz), 6.81(1H, dd, J=8.1, 1.3 Hz),6.84(1H, d, J=1.3 Hz), 7.40(1H, dd, J=8.1, 1.8 Hz), 7.65(1H, d, J=1.8Hz)

EXAMPLE 62

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide ##STR135##

The title compound was obtained as a pale-yellow powder in a similarmanner to that of Example 53 (yield: 100%).

M.P.: 184° to 186° C.

MASS: 316(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.50(2H, d, J=5.7 Hz), 6.23(2H, s), 6.47(1H, m), 6.67(1H,d, J=8.6 Hz), 6.92(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.4, 2.2 Hz),7.37(1H, d, J=2.2 Hz), 7.41(1H, dd, J=8.6, 2.0 Hz), 7.67(1H, d, J=2.0Hz)

EXAMPLE 63

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide ##STR136##

The title compound was obtained as a yellow powder in a similar mannerto that of Example 53 (yield: 79%).

M.P.: 194° to 198° C.

MASS: 336 (M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.90(3H, s), 4.53(2H, d, J=5.7 Hz), 6.50-6.64(3H, m), 6.66(1H, d, J=9.2Hz), 6.91(1H, d, J=8.4 Hz), 7.23(1H, dd, J=8.4, 2.2 Hz), 7.38(1H, d,J=2.6 Hz), 8.08(1H, dd, J=9.2, 2.6 Hz), 8.34(1H, d, J=2.4 Hz)

EXAMPLE 64

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-dimethylsulfamoylbenzamide##STR137##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Example 53 (yield: 93%).

M.P.: 195° to 199° C.

MASS: 398(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

2.66(6H, s), 3.89(3H, s), 4.51(2H, d, J=5.9 Hz), 6.26(2H, s), 6.72(1H,d, J=8.8 Hz), 6.89(1H, d, J=8.4 Hz), 6.89(1H, t, J=5.9 Hz), 7.24(1H, dd,J=8.4, 2.2 Hz), 7.39(1H, d, J=2.2 Hz), 7.54(1H, dd, J=8.8, 2.0 Hz),7.84(1H, d, J=2.0 Hz)

EXAMPLE 65

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-methylsulfamoylbenzamide##STR138##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Example 53 (yield: 78%).

M.P.: 154° to 155° C.

MASS: 873(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

2.57(3H, d, J=5.5 Hz), 3.87(3H, s), 4.47(2H, d, J=5.9 Hz), 4.66(1H, q,J=5.5 Hz), 6.26(2H, s), 6.68(1H, d, J=8.6 Hz), 6.86(1H, d, J=8.6 Hz),7.01(1H, t, J=5.9 Hz), 7.20(1H, dd, J=8.6, 2.2 Hz), 7.36(1H, d, J=2.2Hz), 7.57(1H, dd, J=8.6, 2.2 Hz), 7.93(1H, d, J=2.2 Hz)

EXAMPLE 66

2-Amino-N-(3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide ##STR139##

N-(3,4-Methylenedioxybenzyl)-2-nitro-5-(1-pyrazolyl)benzamide (1.80 g)was dissolved in 120 ml of tetrahydrofuran, followed by the addition of1.8 g of 10% palladium/carbon (water-containing one). The obtainedmixture was subjected to catalytic reduction under the conditions ofroom temperature and one atm. After 13 hours, the reaction mixture wasfreed from the catalyst by filtration and concentrated in a vacuum.Ether was added to the obtained residue to conduct crystallization. Theformed crystals were recovered by filtration to give 1.50 g of the titlecompound as a white powder (yield: 91%).

M.P.: 146° to 147° C.

MASS: 336(M⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.50(2H, d, J=5.7 Hz), 5.65(2H, s), 5.95(2H, s), 6.42(1H, dd, J=2.4, 1.8Hz), 6.75(1H, d, J=8.8 Hz), 6.77(1H, d, J=8.2 Hz), 6.81(1H, dd, J=8.2,1.6 Hz), 6.85(1H, d, J=1.6 Hz), 7.41(1H, dd, J=8.8, 2.4 Hz), 7.65(1H, d,J=1.8 Hz), 7.69(1H, d, J=2.4 Hz), 7.76(1H, d, J=2.4 Hz)

EXAMPLE 67

2-Amino-N-(3,4-methylenedioxybenzyl)-5-(1,2,4-triazol-1-yl)benzamide##STR140##

The title compound was obtained as a white powder in a similar manner tothat of Example 66 (yield: 94%).

M.P.: 163° to 164° C.

MASS: 338(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.51(2H, d, J=5.5 Hz), 5.79(2H, s), 5.96(2H, s), 6.48(1H, s), 6.78(1H,d, J=8.2 Hz), 6.78(1H, d, J=8.9 Hz), 6.81(1H, dd, J=8.2, 1.6 Hz),6.85(1H, d, J=1.6 Hz), 7.41(1H, dd, J=8.9, 2.4 Hz), 7.62(1H, d, J=2.4Hz), 8.03(1H, s), 8.37(1H, s)

EXAMPLE 68

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyano-4-methoxybenzamide##STR141##

2-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)-4-methoxybenzamide (4.67 g)was dissolved in 10 ml of N-methyl-2-pyrrolidone, followed by theaddition of 1.15 g of cuprous cyanide. The obtained mixture was stirredat 180° C. for 4 hours, followed by the addition of an aqueous solutionof ethylenediamine. The obtained mixture was extracted with ethylacetate. The organic phase was washed with water and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate (3:2)). The obtainedsolid was washed with ether to give 1.58 g of the title compound as aslightly yellow powder (yield: 39%).

M.P.: 184° to 185° C.

MASS: 346(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.88(3H, s), 3.90(3H, s), 4.48(2H, d, J=5.9 Hz), 6.08(1H, s),6.32-6.42(3H, m), 6.91(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.4, 2.2 Hz),7.36(1H, d, J=2.2 Hz), 7.59(1H, s)

EXAMPLE 69

7-Amino-4-bromo-N-(3,4-methylenedioxybenzyl)isoindoline-1-one ##STR142##

7-Amino-4-bromoisoindoline (0.35 g) was suspended in 50 ml ofN,N-dimethylformamide, followed by the addition of 0.29 g of 60% sodiumhydride. The obtained mixture was stirred at room temperature for 45minutes, followed by the addition of 0.29 g of piperonyl chloride. Theobtained mixture was stirred at room temperature for 4 hours, followedby the addition of ice-water. The resulting mixture was extracted withethyl acetate. The organic phase was washed with 1N hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate, waterand a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent: n-hexane/ethylacetate (3:1)). The obtained solid was washed with n-hexane to give 0.25g of the title compound as a pale-yellow powder (yield: 46%).

M.P.: 151° to 153° C.

MASS: 361(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

4.08(2H, s), 4.63(2H, s), 5.26(2H, s), 5.95(2H, s), 6.50(1H, d, J=8.6Hz), 6.76-6.79(3H, m), 7.28(1H, d, J=8.6 Hz)

EXAMPLE 70

8-Amino-5-bromo-N-(3,4-methylenedioxybenzyl) ##STR143##

The title compound was obtained as a slightly yellow powder in a similarmanner to that of Example 69 (yield: 84%).

¹ H-NMR(400 MHz, CDCl₃) δ:

2.94(2H, t, J=6.6 Hz), 3.40(2H, t, J=6.6 Hz), 4.63(2H, s), 5.94(2H, s),6.18(2H, s), 6.46(1H, d, J=8.8 Hz), 6.75(1H, dd, J=7.9, 0.5 Hz),6.78(1H, dd, J=7.9, 1.2 Hz), 6.82(1H, dd, J=1.2, 0.7 Hz), 7.30(1H, d,J=8.8 Hz)

EXAMPLE 71

1- 4-Chloro-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!-4-hydroxypiperidine##STR144##

1- (2-Carboxy-4-chlorophenyl!carbamoyl!-4-hydroxypiperidine (0.5 g),piperonylamine (0.42 ml), 1,3-dicyclohexylcarbodiimide (0.38 g),1-hydroxybenztriazole (0.25 g) and 4-dimethylaminopyridine (25 mg) wereadded to 8 ml of N,N-dimethylformamide. The obtained mixture was stirredat room temperature for 61 hours, followed by the addition of water andethyl acetate. The resulting mixture was filtered to remove insolubles.The organic phase was recovered, washed with 1N hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate, water,and a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent:dichloromethane/methanol (30:1)). The obtained residue was crystallizedfrom n-hexane/ethyl acetate and recrystallized from aqueous ethanol togive 0.39 g of the title compound as a white powder (yield: 53%).

M.P.: 151° to 155° C. (dec.)

MASS: 432(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

0.56(2H, m), 1.74(1H, m), 1.95(2H, m), 3.21(2H, ddd, J=13.6, 9.3, 3.3Hz), 3.83-3.97(3H, m), 4.47(2H, d, J=5.7 Hz), 5.96(2H, s), 6.87(1H, dd,J=7.9, 0.5 Hz), 6.81(1H, dd, J=7.9, 1.6 Hz), 6.85(1H, dd, J=1.6, 0.5Hz), 7.03(1H, t, J=5.7 Hz), 7.25(1H, dd, J=9.2, 2.4 Hz), 7.33(1H, d,J=2.4 Hz), 8.21(1H, d, J=9.2 Hz), 10.57(1H, s)

EXAMPLE 72

Ethyl 1- 4-bromo-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylate##STR145##

Ethyl 1- (4-bromo-2-carboxyphenyl!carbamoyl!-piperidine-4-carboxylate(1.2 g), piperonylamine (0.56 ml), 1,3-dicyclohexylcarbodiimide (0.68g), 1-hydroxybenztriazole (0.45 g) and 4-dimethylaminopyridine(catalytic amount) were added to 10 ml of N,N-dimethylformamide. Theobtained mixture was stirred at room temperature for 20 hours, followedby the addition of water and ethyl acetate. The resulting mixture wasfiltered to remove insolubles. The organic phase was recovered, washedwith 1N hydrochloric acid, water, a saturated aqueous solution of sodiumhydrogencarbonate, water, and a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate, and concentrated in avacuum. The obtained residue was purified by silica gel columnchromatography (solvent: n-hexane/ethyl acetate (2:1)). The obtainedsolid was washed with ether to give 1.27 g of the title compound as awhite powder (yield: 77%).

M.P.: 156° to 159° C.

MASS: 532(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, t, J=7.1 Hz), 1.75(2H, m), 1.99(2H, m), 2.52(1H, m), 3.05(2H,m), 4.09(2H, m), 4.16(2H, q, J=7.1 Hz), 4.47(2H, d, J=5.7 Hz), 5.97(2H,s), 6.79(1H, dd, J=8.1, 0.5 Hz), 6.82(1H, dd, J=8.1, 1.5 Hz), 6.85(1H,dd, J=1.5, 0.5 Hz), 6.89(1H, t, J=5.7 Hz), 7.39(1H, dd, J=9.0, 2.4 Hz),7.46(1H, d, J=2.4 Hz), 8.19(1H, d, J=9.0 Hz), 10.57(1H, s)

EXAMPLE 73

1- 4-Chloro-2-(3-chloro-4-methoxybenzyl)carbamoyl!phenyl!carbamoyl!-4-hydroxypiperidine##STR146##

1- (2-Carboxy-4-Chlorophenyl!carbamoyl!-4-hydroxypiperidine (0.5 g),3-chloro-4-methoxybenzylamine hydrochloride (0.7 g),1,3-dicyclohexylcarbodiimide (0.38 g), 1-hydroxybenztriazole (0.25 g),4-dimethylaminopyridine (25 mg) and triethylamine (0.47 ml) were addedto 8 ml of N,N-dimethylformamide. The obtained mixture was stirred atroom temperature for 61 hours, followed by the addition of water andethyl acetate. The obtained mixture was filtered to remove insolubles.The organic phase was recovered, washed with 1N hydrochloric acid,water, a saturated aqueous solution of sodium hydrogencarbonate, water,and a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate, and concentrated in a vacuum. The residue waspurified by silica gel column chromatography (solvent:dichloromethane/methanol (30:1)). The obtained residue was crystallizedfrom n-hexane/ethyl acetate and recrystallized from aqueous ethanol togive 0.51 g of the title compound as a white powder (yield: 66%).

M.P.: 173° to 174° C. (dec.)

MASS: 452(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.33(2H, m), 1.76(2H, m), 3.11(2H, ddd, J=13., 9.5, 3.1 Hz),3.64-3.78(3H, m), 3.84(3H, s), 4.40(2H, d, J=5.7 Hz), 4.46(1H, d, J=4.2Hz), 7.11(1H, d, J=8.6 Hz), 7.28(1H, dd, J=8.6, 2.2 Hz), 7.41(1H, d,J=2.2 Hz), 7.50(1H, dd, J=9.2, 2.6 Hz), 7.82(1H, d, J=2.6 Hz), 8.32(1H,d, J=9.2 Hz), 9.37(1H, t, J=5.7 Hz), 11.02(1H, s)

EXAMPLE 74

1- 2-(3-Chloro-4-methoxybenzyl)carbamoyl!-4-cyanophenyl!carbamoyl!-4-hydroxypiperidine##STR147##

The title compound was obtained as a white powder in a similar manner tothat of Example 73 (yield: 13%).

M.P.: 194° to 196° C.

MASS: 443(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.35(2H, m), 1.77(2H, m), 3.16(2H, m), 3.64-3.80(3H, m), 3.84(3H, s),4.42(2H, d, J=5.5 Hz), 4.77(1H, d, J=4.2 Hz), 7.11(1H, d, J=8.4 Hz),7.29(1H, dd, J=8.9, 2.0 Hz), 7.43(1H, d, J=2.0 Hz), 7.86(1H, dd, J=9.0,1.6 Hz), 8.24(1H, d, J=1.6 Hz), 8.49(1H, d, J=9.0 Hz), 9.42(1H, m),11.47(1H, s)

EXAMPLE 75

Ethyl 1- 4-bromo-2-(3-chloro-4-methoxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylate##STR148##

Ethyl 1- (4-bromo-2-carboxyphenyl!carbamoyl!-piperidine-4-carboxylate(1.0 g), 3-chloro-4-methoxy benzylamine (0.78 g),1,3-dlcyclohexylcarbodiimide (0.57 g), 1-hydroxybenztriazole (0.37 g),4-dimethyl-aminopyriding (catalytic amount), and triethyiamine (0.52 ml)were added to 8 ml of N,N-dimethylformamide. The obtained mixture wasstirred at room temperature for 66 hours, followed by the addition ofwater and ethyl acetate. The resulting mixture was filtered to removeinsolubles. The organic phase was recovered, washed with 1N hydrochloricacid, water, a saturated aqueous solution of sodium hydrogencarbonate,water, and a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate, and concentrated in a vacuum. The residuewas purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (2:1)). The obtained solid was washed with etherto give 1.00 g of the title compound as a white powder (yield: 72%).

M.P.: 172° to 174° C.

MASS: 554(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, t, J=7.1 Hz), 1.75(2H, m), 1.99(2H, m), 2.52(1H, m), 3.05(2H,m), 3.91(3H, s), 4.08(2H, m), 4.16(2H, q, J=7.1 Hz), 4.47(2H, d, J=5.7Hz), 6.92(1H, d, J=8.4 Hz), 7.22(1H, m), 7.22(1H, dd, J=8.4, 2.2 Hz),7.33(1H, dd, J=9.2, 2.4 Hz), 7.41(1H, d, J=2.2 Hz), 7.45(1H, d, J=2.4Hz), 8.10(1H, d, J=9.2 Hz), 10.53(1H, s)

EXAMPLE 76

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-(piperidineoacetamido)benzamide##STR149##

5-Chloro-2-chloroacetamido-N-(3-chloro-4-methoxybenzyl)benzamide (0.7g), piperidine (0.51 ml), anhydrous potassium carbonate (0.72 g) andtetra(n-butyl)ammonium iodide (catalytic amount) were added to 6 ml ofN,N-dimethylformamide. The obtained mixture was stirred at roomtemperature for 1.5 hours, followed by the addition of water. Theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with water and a saturated aqueous solution of common salt,dried over anhydrous magnesium sulfate, and concentrated in a vacuum.The residue was purified by silica gel column chromatography (solvent:n-hexane/ethyl acetate (3:1)) and recrystallized from aqueous ethanol togive 0.37 g of the title compound as a white needle (yield: 48%).

M.P.: 126° to 129° C.

MASS: 450(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.42-1.50(2H, m), 1.66-1.74(4H, m), 2.46-2.56(4H, m), 3.07(2H, s),3.90(3H, s), 4.53(2H, d, J=5.7 Hz), 6.62(1H, t, J=5.9 Hz), 6.89(1H, d,J=8.4 Hz), 7.20(1H, dd, J=8.4, 2.2 Hz), 7.32(1H, dd, J=9.0, 2.0 Hz),7.36(1H, d, J=2.2 Hz), 7.40(1H, d, J=2.4 Hz), 8.49(1H, d, J=9.0 Hz),11.52(1H, s)

EXAMPLE 77

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-(pyrrolidinoacetamido)benzamide##STR150##

The title compound was obtained as a slightly yellow prism in a similarmanner to that of Example 24 (yield: 86%).

M.P.: 98° to 100° C.

MASS: 436(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.81-1.92(4H, m), 2.61-2.72(4H, m), 3.28(2H, s), 3.89(3H, s), 4.49(2H,d, J=5.9 Hz), 6.88(1H, d, J=8.4 Hz), 6.89(1H, t, J=5.9 Hz), 7.19(1H, dd,J=8.4, 2.2 Hz), 7.27(1H, dd, J=9.0, 2.4 Hz), 7.35(1H, d, J=2.2 Hz),7.41(1H, d, J=2.4 Hz), 8.42(1H, d, J=9.0 Hz), 11.49(1H, s)

EXAMPLE 78

5-Chloro-N-(3,1-methylenedioxybenzyl)-2-(pyrrolidinoacetamido)benzamide##STR151##

The title compound was obtained as a slightly yellow needle in a similarmanner to that of Example (yield: 60%).

M.P.: 136° to 141° C.

MASS: 444(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.40-1.48(2H m); 1.56-1.64(4H, m), 2.44(4H, s), 2.56(2H, t, J=7.0 Hz),2.70(2H, t, J=7.0 Hz), 4.48(2H, d, J=5.7 Hz), 5.97(2H, s), 6.26(1H, m),6.78(1H, d, J=7.8 Hz), 6.80(1H, d, J=7.8 Hz), 6.83(1H, s), 7.35(1H, dd,J=9.0, 2.4 Hz), 7.40(1H, d, J=2.4 Hz), 8.81(1H, d, J=9.0 Hz), 11.03(1H,s)

EXAMPLE 79

5-Chloro-N-(3,4-methylenedioxybenzyl)-2-(4-piperidinobutyrylamino)benzamide##STR152##

The title compound was obtained as a slightly yellow needle in a similarmanner to that of Example (yield: 7%).

M.P.: 121° to 122° C.

MASS: 458(MH⁺) ¹ H-NMR(400 MHz, CDCl₃) δ:

1.37-1.45(2H, m), 1.51-1.59(4H, m), 1.91(2H, quintet, J=7.5Hz),2.31-2.48(8H, m), 4.50(2H, d, J=5.7Hz), 5.98(2H, s), 6.43(1H, m),6.78-6.85(3H, m), 7.39(1H, d, J=2.6Hz), 7.89(1H, dd, J=9.7, 2.6 Hz),8.56(1H, d, J=9.7Hz), 10.96(1H, s)

EXAMPLE 80

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(isonicotinoylamino)benzamide##STR153##

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide (0.33 g) wasdissolved in 5 ml of pyridine, followed by cooling with ice.Isonicotinoyl chloride hydrochloride (0.2 g) was added to the resultingsolution. The obtained mixture was stirred at room temperature for 4hours, followed by the addition of water. The precipitates formed wererecovered by filtration, washed with water and ether, and recrystallizedfrom ethyl acetate to give 0.27 g of the title compound as a slightlyyellow needle (yield: 64%).

M.P.: 243° to 245° C. (dec.)

MASS: 421(MR⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.83(3H, s), 4.47(2H, d, J=5.7 Hz), 7.32(1H, dd, J=8.4, 2.2 Hz),7.46(1H, d, J=2.2 Hz), 7.79-7.83(2H, m), 8.06(1H, dd, J=8.8, 1.8 Hz),8.40(1H, d, J=1.8 Hz), 8.77(1H, d, J=8.8 Hz), 8.84-8.88(2H, m), 9.56(1H,t, J=5.7 Hz), 12.90(1H, s)

EXAMPLE 81

5-Bromo-N-(3-chloro-4-methoxybenzyl-2-(isonicotinoylamino)benzamide##STR154##

The title compound was obtained as a white needle in a similar manner tohat of Example 80 (yield: 7s).

M.P.: 190° to 192° C.

MASS: 476(MH⁺)

¹ H-NMR(400MHz, CDCl₃) δ:

3.90(3H, s), 4.57(2H, d, J=5.7 Hz), 6.70(1H, t, J=5.7 Hz), 6.92(1H, d,J=8.4 Hz), 7.23(1H, dd, J=8.4, 2.2 Hz), 7.40(1H, d, J=2.2 Hz), 7.64(1H,dd, J=9.3, 2.2 Hz), 7.65(1H, d, J=2.2 Hz), 7.83-7.87(2H, m), 8.72(1H, d,J=9.3 Hz), 8.81-8.85(2H, m), 12.33(1H, s)

EXAMPLE 82

5-Bromo-N-(3-chloro-4-methoxybenzyl)-2-(isonicotinoylamino)-4-methoxybenzamide##STR155##

The title compound was obtained as a white needle in a similar manner tothat of Example 80 (yield: 40%).

M.P.: 252° to 253° C. (dec.)

MASS: 506(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.83(3H, s), 3.95(3H, s), 4.45(2H, d, J=5.7 Hz), 7.11(1H, d, J=8.6 Hz),7.30(1H, dd, J=8.6, 2.2 Hz), 7.42(1H, d, J=2.2 Hz), 7.80-7.84(2H, m),8.24(1H, s), 8.55(1H, s), 8.84-8.88(2H, m), 9.39(1H, t, J=5.7 Hz),13.26(1H, s)

EXAMPLE 83

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(isonicotinoylamino)-4-methoxybenzamide##STR156##

The title compound was obtained as a white needle in a similar manner tothat of Example 80 (yield: 81%).

M.P.: 262° to 267° C. (dec.)

MASS: 451(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.83(3H, s), 4.00(3H, s), 4.46(2H, d, J5.7 Hz), 7.11(1H, d, J=8.6 Hz),7.81(1H, dd, J=8.6, 2.2 Hz), 7.44(1H, d, J=2.2 Hz), 7.81-7.84(2H, m),8.40(1H, s), 8.60(1H, s), 8.85-8.90(2H, m), 9.42(1H, t, J=5.7 Hz),13.48(1H, s)

EXAMPLE 84

5-Bromo-2-(isonicotinoylamino)-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide##STR157##

The title compound was obtained as a slightly yellow needle in a similarmanner to that of Example 30(yield: 75%)

¹ H-NMR(400 MHz, DMSO-d₆)

M.P.: 249° to 254° C. (dec.)

MASS: 484(M^(H+))

3.94(3H, s), 4.42(2H, d, J=5.7 Hz), 5.98(2H, s), 6.83(1H, dd, J=8.0, 1.3Hz), 6.86(1H, dd, J=8.0, 0.4 Hz), 6.94(1H, dd, J=1.3, 0.4 Hz),7.80-7.84(2H, m), 8.24(1H, s), 8.55(1H, s), 8.85-8.88(2H, m), 9.36(1H,t, J=5.7 Hz), 13.32(1H, s)

EXAMPLE 85

5-Bromo-2-(isonicotinoylamino)-N-(3,4-methylenedioxybenzyl)benzamide##STR158##

The title compound was obtained as a slightly yellow needle in a similarmanner to that of Example 80 (yield: 49%).

M.P.: 207° to 211° C.

MASS: 454 (H⁺)

¹ H-NMR(400 Hz, DMSO-d₆) δ:

4.42(2H, d, J=5.7 Hz), 5.98(2H, s), 6.83(1H, dd, J=7.9, 1.5 Hz),6.86(1H, d, J=7.9 Hz), 6.95(1H, d, J=1.5 Hz), 7.75-7.83(3H, m), 8.10(1H,d, J=2.2 Hz), 8.53(1H, d, J=9.0 Hz), 8.81-8.87(2H, m), 9.48(1H, t, J=5.7Hz), 12.61(1H, s)

EXAMPLE 86

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-cyanocyclohexanecarbonyl)amino!benzamide ##STR159##

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide (0.5 g) wasdissolved in 8 ml of pyridine, followed by cooling with ice. A solutionof 0.33 g of trans-4-cyanocyclohexanecarbonyl chloride in 1 ml ofdichloromethane was dropped into the above solution in such a way thatthe bulk temperature did not exceed 10° C. The obtained mixture wasstirred for 2 hours, followed by the addition of ice-water. Theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with 1N hydrochloric acid, water, a saturated aqueoussolution of sodium hydrogen-carbonate, water, and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (solvent: dichloromethane/methanol (100: 1)) andrecrystallized from aqueous ethanol to give 0.44 g of the title compoundas a white needle (yield: 61%).

M.P.: 188° to 184° C.

MASS: 451(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.54-1.75(4H, m), 2.08-2.18(2H, m), 2.20-2.28(2H, m), 2.89(1H, m),2.51(1H, m), 8.91(8H, s), 4.53(2H, d, J=5.7 Hz), 8.92(1H, t, J=5.7 Hz),6.93(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.4, 2.2 Hz), 7.39(1H, d, J=2.2Hz), 7.70(1H, dd, J=8.0, 2.0 Hz), 7.86(1H, d, J=2.0 Hz), 8.79(1H, d,J=8.8 Hz), 11.57(1H, s)

EXAMPLE 87

5-Bromo-2-(tans-4-cyanocyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR160##

The title compound was obtained as a white granular crystal in a similarmanner to that of Example 86 (yield: 75).

M.P.: 147° to 149° C.

MASS: 484(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.54-1.73(4H, m), 2.07-2.14(2H, m), 2.19-2.27(2H, m), 2.35(1H, m),2.50(1H, m), 4.51(2H, d, J=5.5 Hz), 5.98(2H, s), 6.47(1H, m), 6.80(2H,s), 6.84(1H, s), 7.55(1H, dd, J=9.5, 2.2 Hz), 7.55(1H, d, J=2.2 Hz),8.52(1H, d, J=9.5 Hz), 11.13(1H, s)

EXAMPLE 88

2-(trans-4-(Acetoxy)cyclohexancarbonyl)-amino!-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide##STR161##

The title compound was obtained as a white needle in a similar manner tothat of Example 34 (yield: 60%).

M.P.: 194° to 196° C.

MASS: 484(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.39-1.50(2H, m), 1.62-1.74(2H, m), 2.05(3H, s), 2.05-2.15(4H, m),2.34(1H, tt, J=11.7, 3.3 Hz), 3.91(3H, s), 4.54(2H, d, J=5.9 Hz),4.73(1H, tt, J=11.0, 4.0 Hz), 6.82(1H, t, J=5.9 Hz), 6.93(1H, d, J=8.4Hz), 7.23(1H, dd, J=8.4, 2.2 Hz), 7.40(1H, d, J=2.2 Hz), 7.70(1H, dd,J=8.8, 2.0 Hz), 7.83(1H, d, J=2.0 Hz), 8.81(1H, d, J=8.8 Hz), 11.47(1H,s)

EXAMPLE 89

5-Chloro-N-(3,4-methylenedioxybenzyl-2-(trans-4-piperidinocyclohexanecarbonyl)amino!benzamide ##STR162##

The title compound was obtained as a slightly yellow needle in a similarmanner to that of Example 86 (yield: 17%).

M.P.: 162° to 163° C.

MASS: 498(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.29-1.48(4H, m), 1.50-1.63(6H, m), 2.00(2H, m), 2.10(2H, m), 2.22(1H,m), 2.32(1H, m), 2.46-2.58(4H, m), 4.51(2H, d, J=5.7 Hz), 5.97(2H, s),6.51(1H, t, J=5.7 Hz), 6.77-6.85(3H, m), 7.38(1H, dd, J=8.6, 2.6 Hz),7.39(1H, d, J=2.6 Hz), 8.57(1H, d, J=8.6 Hz), 10.94(1H, s)

EXAMPLE 90

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-piperidinocyclohexanecarbonyl)amino!benzamide ##STR163##

The title compound was obtained as a white needle in a similar manner tothat of Example 86 (yield: 2%).

M.P.: 215° to 218° C. (dec.)

MASS: 509(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.31-1.48(4H, m), 1.51-1.64(4H, m), 2.01(2H, m), 2.11(2H, m),2.22-2.38(2H, m), 2.48-2.56(4H, m), 3.91(3H, s), 4.54(2H, d, J=5.7 Hz),6.71(114, t, J=5.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.4, 2.2Hz), 7.40(1H, d, J=8.8, 2.0 Hz), 7.79(1H, d, J=2.0 Hz), 8.81 (1H, d,J=8.8 Hz), 11.34(1H, s)

EXAMPLE 91

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR164##

2-Amino-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide (1.2 g) wasdissolved in 10 ml of pyridine, followed by cooling with ice. A solutionof 1.0 g of trans-4-(ethoxycarbonyl)cyclohexanecarbonyl chloride in 2 mlof dichloromethane was dropped into the solution prepared above in sucha way that the bulk temperature did not exceed 10° C. The obtainedmixture was stirred for 4 hours, followed by the addition of ice-water.The resulting mixture was extracted with ethyl acetate. The organicphase was washed with 1N hydrochloric acid, water, a saturated aqueoussolution of sodium hydrogencarbonate, water, and a saturated aqueoussolation of common salt, dried over anhydrous magnesium sulfate, andconcentrated in a vacuum. The residue was purified by silica gel columnchromatography (solvent: n-hexane/ethylacetate (2: 1)). The obtainedsolid was washed with ether to give 0.9 g of the title compound as awhite powder (yield: 48% ).

M.P.: 153° to 155° C.

MASS: 498(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.64(4H, m), 2.05-2.19(4H, m), 2.28-2.38(2H,m), 3.91(3H, s), 4.14(2H, q, J=7.1 Hz), 4.54(2H, d, J=5.7 Hz), 6.82(1H,t, J=5.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.23(1H, dd, J=8.4, 2.2 Hz),7.40(1H, d, J=2.2 Hz), 7.69(1H, dd, J=9.0, 1.8 Hz), 7.83(1H, d, J=1.8Hz), 8.81(1H, d, J=9.0 Hz), 11.45(1H, s)

EXAMPLE 92

N-(3-Chloro-4-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-5-nitrobenzamide##STR165##

The title compound was obtained as a pale-yellow powder in a similarmanner to that of Example 91 (yield: 614%).

M.P.: 166° to 169° C.

MASS: 518(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(8H, t, J=7.1 Hz), 1.47-1.66(4H, m), 2.07-2.20(4H, m), 2.29-2.40(2H,m), 8.91(8H, s), 4.14(2H, q, J=7.1 Hz), 4.57(2H, d, J=5.7 Hz), 6.79(1H,t, J=8.4 Hz), 6.98(1H, d, J=8.4 Hz), 7.24(1H, dd, J=8.4, 2.2 Hz),7.41(1H, d, J=2.2 Hz), 8.80(1H, dd, J=9.3, 2.6 Hz), 8.39(1H, d, J=2.6Hz), 8.88(1H, d, J=9.3 Hz), 11.64(1H, s)

EXAMPLE 93

5-Chloro-N-(3-chloro-4-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR166##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 83%).

M.P.: 122° to 125° C.

MASS: 507(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.43-1.63(4H, m), 2.06-2.14(4H, m), 2.24-2.36(2H,m), 3.91(3H, s), 4.13(2H, q, J=7.1 Hz), 4.52(2H, d, J=5.7 Hz), 6.67(1H,t, J=5.7 Hz), 6.92(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.4, 2.2 Hz),7.37(1H, d, J=2.2 Hz), 7.38(1H, dd, J=9.0, 2.4 Hz), 7.42(1H, d, J=2.4Hz), 8.55(1H, d, J=9.0 Hz), 10.99(1H, s)

EXAMPLE 94

5-Chloro-2- (trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(2-methoxy-5-pyridyl)methyl!benzamide ##STR167##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 94%).

M.P.: 141° to 144° C.

MASS: 474(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, , J=7.1 Hz), 1.45-1.63(4H, m), 2.04-2.18(4H, m), 2.24-2.36(2H,m), 3.94(3H, s), 4.14(2H, q, J=7.1 Hz), 4.54(2H, d, J=5.7 Hz), 6.55(1H,t, J=5.7 Hz), 6.76(1H, d, J=8.6 Hz), 7.39(1H, d, J=2.4 Hz), 7.40(1H, dd,J=9.7, 2.4 Hz), 7.59(1H, dd, J=8.6, 2.6 Hz), 8.16(1H, d, J=2.6 Hz),8.58(1H, d, J=9.7 Hz), 10.98(1H, s)

EXAMPLE 95

5-Chloro-N-(3-cyano-4-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR168##

The title compound was obtained as a white powder in a similar manner tothat of example 91 (yield:

M.P.: 157° to 160° C.

*Ms: 496(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.44-1.62(4H, m), 2.03-2.17(4H, m), 2.24-2.36(2H,m), 3.94(3_(H), s), 4.13(2H, q, J=7.1 Hz), 4.55(2H, d, J=5.9 Hz),6.85(1H, t, J=5.9 Hz), 6.98(1H, m), 7.39(1H, dd, J=9.0, 2.4 Hz),7.44(1H, d, J=2.4 Hz), 7.53-7.58(2H, m), 8.56(1H, d, J=9.0 Hz),11.00(1H, s)

EXAMPLE 96

5-Chloro-N-(4-chloro-3-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR169##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 83%).

M.P.: 167° to 168° C.

MASS: 507(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.44-1.64(4H, m), 2.04-2.18(4H, m), 2.25-2.36(2H,m), 3.92(3H, s), 4.13(2H, q, J=7.1 Hz), 4.58(2H, d, J=5.7 Hz), 6.54(1H,t, J=5.7 Hz), 6.88(1H, dd, J=8.1, 1.6 Hz), 6.91(1H, d, J=1.6 Hz),7.36(1H, d, J=8.1 Hz), 7.42(1H, d, J=2.2 Hz), 7.42(1H, dd, J=9.5, 2.2Hz), 8.60(1H, d, J=9.5 Hz), 10.99(1H, s)

EXAMPLE 97

5-Bromo-N-(3-chloro-5-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-4-methoxybenzamide##STR170##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 76%).

M.P.: 160° C. (dec.)

MASS: 583(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.65(4H, m), 2.08-2.16(4H, m), 2.27-2.37(2H,m), 3.91(3H, s), 3.95(3H, s), 4.13(2H, q, J=7.1 Hz), 4.51(2H, d, J=5.5Hz), 6.41(1H, t, J=5.5 Hz), 6.92(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.4,2.2 Hz), 7.37(1H, d, J=2.2 Hz), 7.61(1H, s), 8.52(1H, s), 11.62(1H, s)

EXAMPLE 98

5-Bromo-4-methoxy-N-(3-chloro-4-methoxybenzyl-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR171##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 71%).

M.P.: 171° to 173° C.

MASS: 553(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.43-1.62(4H, m), 2.03-2.16(4H, m), 2.24-2.35(2H,m), 3.90(3H, s), 4.13(2H, q, J=7.1 Hz), 4.52(2H, d, J=5.7 Hz), 6.79(1H,t, J=5.7 Hz), 6.91(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.4, 2.2 Hz),7.37(1H, d, J=2.2 Hz), 7.50(1H, dd, 9.0, 2.4 Hz), 7.57(1H, d, J=2.4 Hz),8.47(1H, d, J=9.0 Hz), 11.01(1H, s)

EXAMPLE 99

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-4-methoxybenzamide##STR172##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 72%).

M.P.: 193° to 195° C.

MASS: 526(M^(H+))

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.65(4H, m), 2.06-2.19(4H, m), 2.28-2.39(2H,m), 3.91(3H, s), 3.98(3H, s), 4.14(2H, q, J=7.1 Hz), 4.51(2H, d, J=5.7Hz), 6.66(1H, t, J=5.7 Hz), 6.93(1H, d, J=8.6 Hz), 7.22(1H, dd, J=8.6,2.2 Hz), 7.39(1H, d, J=2.2 Hz), 7.75(1H, s), 8.58(1H, s), 11.92(1H, s)

EXAMPLE 100

N-(3-Chloro-4-methoxybenzyl)-5-dimethylsulfamoyl-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide ##STR173##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 89%).

M.P.: 197° to 198° C.

MASS: 580(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, t, J=7.1 Hz), 1.47-1.65(4H, m), 2.06-2.19(4H, m), 2.29-2.39(2H,m), 2.67(6H, s), 3.90(3H, s), 4.14(2H, q, J=7.1 Hz), 4.56(2H, d, J=5.9Hz), 6.90(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.4, 2.2 Hz), 7.32(1H, t,J=5.9 Hz), 7.42(1H, d, J=2.2 Hz), 7.79(1H, dd, J=9.0, 2.2 Hz), 7.99(1H,d, J=2.2 Hz), 8.88(1H, d, J=9.0 Hz), 11.63(1H, s)

EXAMPLE 101

N-(3-Chloro-4-methoxybenzyl)-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-5-methylsulfamoylbenzamide##STR174##

The title compound was obtained as a white powder in a similar manner tothat of Example 91 (yield: 44%).

M.P.: 190° to 191° C.

MASS: 566(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, t, J=7.1 Hz), 1.46-1.65(4H, m), 2.06-2.18(4H, m), 2.29-2.39(2H,m), 2.61(3H, d, J=5.3 Hz), 8.89(3H, s), 4.14(2H, q, J=7.1 Hz), 4.58(2H,d, J=5.9 Hz), 4.65(1H, q, J=5.3 Hz), 6.89(1H, d, J=8.6 Hz), 7.20(1H, t,J=5.9 Hz), 7.23(1H, dd, J=8.6, 2.2 Hz), 7.40(1H, d, J=2.2 Hz), 7.84(1H,dd, J=9.0, 2.2 Hz), 8.03(1H, d, J=2.2 Hz) 8.83(1H, d, J=9.0 Hz),11.58(1H, s)

EXAMPLE 102

2-(trans-4-(Ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide##STR175##

The title compound was obtained as a white powder in a similar manner tothat of Example 88 (yield: 85%).

M.P.: 197° to 201° C.

MASS: 519(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, , J=7.1 Hz), 1.46-1.66(4H, m), 2.08-2.18(4H, m), 2.27-2.38(2H,m), 4.14(2H, q, J=7.1 Hz), 4.52(2H, d, J=5.7 Hz), 5.96(2H, s), 6.47(1H,dd, J=2.4, 1.6 Hz), 6.78(1H, d, J=7.9 Hz), 6.80(1H, dd, J=7.9, 1.6 Hz),6.84(1H, d, J=1.6 Hz), 6.85(1H, m), 7.59(1H, dd, J=9.2, 2.6 Hz),7.68(1H, d, J=1.6 Hz), 7.89(1H, d, J=2.6 Hz), 7.95(1H, d, J=2.4 Hz),8.73(1H, d, J=9.2 Hz), 11.18(1H, s)

EXAMPLE 103

2-(trans-4-(Ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-(1,2,4-triazol-1-yl)benzamide##STR176##

The title compound was obtained as a white powder in a similar manner tothat of Example 86 (yield: 69%).

M.P.: 204° to 206° C.

MASS: 520(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.27(3H, t, J=7.1 Hz), 1.45-1.65(4H, m), 2.05-2.19(4H, m), 2.28-2.38(2H,m), 4.14(2H, q, J=7.1 Hz), 4.55(2H, d, J=5.7 Hz), 5.97(2H, s), 6.79(1H,d, J=7.9 Hz), 6.82(1H, dd, J=7.9, 1.6 Hz), 6.85(1H, d, J=1.6 Hz),6.91(1H, t, J=5.7 Hz), 7.64(1H, dd, J=9.2, 2.6 Hz), 7.86(1H, d, J=2.6Hz), 8.05(1H, s), 8.49(1H, s), 8.79(1H, d, J=9.2 Hz), 11.21(1H, s)

EXAMPLE 104

2-(trans-4-(Ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-trifluoromethoxybenzamide##STR177##

The title compound was obtained as a white powder in a similar manner tothat Example 86 (yield: 63%).

M.P.: 179° to 180° C.

MASS: 537(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.44-1.64(4H, m), 2.05-2.17(4H, m), 2.25-2.37(2H,m), 4.13(2H, q, J=7.1 Hz), 4.52(2H, d, J=5.7 Hz), 5.97(2H, s), 6.53(1H,t, J=5.7 Hz), 6.79(1H, d, J=7.9 Hz), 6.81(1H, d, J=7.9 Hz), 6.84(1H, s),7.28(1H, d, J=2.7 Hz), 7.32(1H, dd, J=9.2, 2.7 Hz), 8.66(1H, d, J=9.2Hz), 11.03(1H, s)

EXAMPLE 105

5-Cyano-2-(trans-4-ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR178##

The title compound was obtained as a white powder in a similar manner tothat of Example 86 (yield: 36%).

M.P.: 150° to 153° C.

MASS: 478(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.64(4H, m), 2.05-2.18(4H, m), 2.28-2.38(2H,m), 4.14(2H, q, J=7.1 Hz), 4.52(2H, d, J=5.7 Hz), 5.98(2H, s), 6.75(1H,t, J=5.7 Hz), 6.80(1H, dd, J=7.9, 0.7 Hz), 6.83(1H, dd, J=7.9, 1.3 Hz),6.85(1H, dd, J=1.3, 0.7 Hz), 7.69(1H, dd, J=9.0, 2.0 Hz), 7.81(1H, d,J=2.0 Hz), 8.80(1H, d, J=9.0 Hz), 11.46(1H, s)

EXAMPLE 106

5-Bromo-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide##STR179##

The title compound was prepared as a white powder in a similar manner tothat of Example 86 (yield: 67%).

M.P.: 194° to 195° C.

MASS: 561 (MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.66(4H, m), 2.08-2.16(4H, m), 2.27-2.37(2H,m), 3.95(3H, s), 4.13(2H, q, J=7.1 Hz), 4.50(2H, d, J=5.5 Hz), 5.97(2H,s), 6.35(1H, t, J=5.5 Hz), 6.80(2H, s), 6.84(1H, s), 7.60(1H, s),8.52(1H, s), 11.65(1H, s)

EXAMPLE 107

4-Bromo-7-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)isoindoline-1-one##STR180##

The title compound was obtained as a white powder in a similar manner tothat of Example 86 (yield: 67%).

M.P.: 135° to 137° C.

MASS: 543(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.68(4H, m), 2.10-2.20(4H, m), 2.29-2.41(2H,m), 4.14(2H, q, J=7.1 Hz), 4.17(2H, s), 4.66(2H, s), 5.96(2H, s),6.76-6.82(3H, m), 7.55(1H, d, J=8.8 Hz), 8.44(1H, d, J=8.8 Hz),10.49.(1H, s)

EXAMPLE 108

5-Bromo-8-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydro-1-isoquinoline-1-one##STR181##

The title compound was obtained as a colorless oil in a similar mannerto that of Example 86 (yield: 85%).

MASS: 557(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.46-1.67 (4H, m), 2.06-2.17(4H, m),2.28-2.38(2H, m), 3.01(2H, t, J=6.6 Hz), 3.46(2H, t, J=6.6 Hz), 4.13(2H,q, J=7.1 Hz), 4.67(2H, s), 5.96(2H, s), 6.77(1H, dd, J=7.2, 1.3 Hz),6.79(1H, d, J=7.2 Hz), 6.81(1H, d, J=1.3 Hz), 7.60(1H, d, J=9.0 Hz),8.57(1H, d, J=9.0 Hz), 12.38(1H, s)

EXAMPLE 109

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-hydroxycyclohexanecarbonyl)amino!benzamide ##STR182##

2-(trans-4-(Acetoxy)cyclohexanecarbonyl)amino)-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide(0.9 g) was dissolved in a solvent mixture comprising 10 ml of ethanoland 10 ml of tetrahydrofuran, followed by the addition of 8 ml of 1Nsodium hydroxide. The obtained mixture was stirred at room temperaturefor 2 hours, followed by the addition of water. The resulting mixturewas extracted with an ethyl acetate/tetrahydrofuran/ethanol mixture. Theorganic phase was washed with a saturated aqueous solution of commonsalt, dried over anhydrous magnesium sulfate, and distilled in a vacuumto remove the solvent. The obtained solid was washed with ether andrecrystallized from aqueous ethanol to give 0.33 g of the title compoundas a white needle (yield: 39%).

M.P.: 164° to 165° C.

MASS: 442(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.14-1.26(2H, m), 1.35-1.47(2H, m), 1.83-1.93(4H, m), 3.35(1H, m),3.84(3H, s), 4.42(2H, d, J=5.5 Hz), 4.61(1H, d, J=4.4 Hz), 7.12(1H, d,J=8.4 Hz), 7.30(1H, dd, J=8.4, 2.2 Hz), 7.44(1H, d, J=2.2 Hz), 7.94(1H,dd, J=8.8, 2.0 Hz), 8.25(1H, d, J=2.0 Hz), 8.58(1H, d, J=8.8 Hz),9.24(1H, t, J=5.5 Hz), 11.54(1H, s)

EXAMPLE 110

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide##STR183##

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(trans-4-(ethoxycarbonyl)cyclohexanecarbonyl)amino!benzamide (0.9 g) wasdissolved in a solvent mixture comprising 10 ml of ethanol and 10 ml oftetrahydrofuran, followed by the addition of 8 ml of 1N sodiumhydroxide. The obtained mixture was stirred at room temperature for 8hours, followed by the addition of water and ethyl acetate. The aqueousphase was recovered. The ethyl acetate phase was extracted with water.The obtained aqueous phase and the above one were combined and acidifiedwith 1N hydrochloric acid. The precipitates formed were recovered byfiltration and recrystallized from aqueous ethanol to give 0.42 g of thetitle compound as a white needle (yield: 72%).

M.P.: 223° to 227° C.

MASS: 470(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.48(4H, m), 1.89-2.02(4H, m), 2.18(1H, m), 2.31(1H, m), 3.84(3H,s), 4.43(2H, d, J=5.7 Hz), 7.12(1H, d, J=8.6 Hz), 7.31(1H, dd, J=8.6,2.2 Hz), 7.44(1H, d, J=2.2 Hz), 7.93(1H, dd, J=8.8, 2.0 Hz), 8.26(1H, d,J=2.0 Hz), 8.60(1H, d, J=8.8 Hz), 9.43(1H, t, J=5.7 Hz), 11.57(1H, s),12.10(1H, s)

EXAMPLE 111

1- 4-Bromo-2-(3-chloro-4-methoxybenzyl)carbamoyl!phenyl!carbamoyl!piperidine-4-carboxylicacid ##STR184##

The title compound was obtained as a white powder in a similar manner tothat of Example 110 (yield: 64%).

M.P.: 259° C. (dec.)

MASS: 526(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.48(2H, m), 1.87(2H, m), 2.49(1H, m), 2.98(1H, m), 3.84(3H, s),8.91(2H, m), 4.40(2H, d, J=5.7 Hz), 7.11(1H, d, J=8.6 Hz), 7.28(1H, dd,J=8.6, 2.0 Hz), 7.61(1H, d, J=2.0 Hz), 7.94(1H, d, J=2.4 Hz), 8.26(1H,d, J=9.2 Hz), 9.38(1H, t, J=5.7 Hz), 11.04(1H, s), 12.30(1H, s)

EXAMPLE 112

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-5-chloro-N-(3-chloro-4-methoxybenzyl)benzamide##STR185##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 77%).

M.P.: 233° to 235° C.

MASS: 478 (MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.47(4H, m), 1.85-2.02(4H, m), 2.13-2.29(2H, m), 3.84(3H, s),4.40(2H, d, J=5.7 Hz), 7.11(1H, d, J=8.4 Hz), 7.29(1H, dd, J=8.4, 2.2Hz), 7.41(1H, d, J=2.2 Hz), 7.55(1H, dd, J=9.0, 2.4 Hz), 7.82(1H, d,J=2.4 Hz), 8.39(1H, d, J=9.0 Hz), 9.35(1H, t, J=5.7 Hz), 11.15(1H, s),12.08(1H, s)

EXAMPLE 113

5-Bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)benzamide##STR186##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 58%).

M.P.: 247° to 250° C.

MASS: 523(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.48(4H, m), 1.88-2.02(4H, m), 2.13-2.29(2H, m), 3.84(3H, s),4.40(2H, d, J=5.7 Hz), 7.11(1H, d, J=8.4 Hz), 7.28(1H, dd, J=8.4, 2.2Hz), 7.41(1H, d, J=2.2 Hz), 7.67(1H, dd, J=9.0, 2.2 Hz), 7.94(1H, d,J=2.2 Hz), 8.33(1H, d, J=9.0 Hz), 9.35(1H, t, J=5.7 Hz), 11.16(1H, s),12.08(1H, s)

EXAMPLE 114

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide##STR187##

The title compound was obtained as a pale-yellow needle in a similarmanner to that of Example 110 (yield: 65%).

M.P.: 285° to 244° C. (dec.)

MASS: 490(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.82-1.50(4H, m), 1.91-2.04(4H, m), 2.18(1H, m), 2.84(1H, m), 8.84(8H,s), 4.45(2H, d, J=5.3 Hz), 7.12(1H, d, J=8.4 Hz), 7.81(1H, dd, J=8.4,2.2 Hz), 7.44(1H, d, J=2.2 Hz), 8.88(1H, dd, J=9.3, 2.7 Hz), 8.68(1H, d,J=9.3 Hz), 8.69(1H, d, J=2.7 Hz), 9.68(1H, t, J=5.3 Hz), 11.76(1H, s),12.10(1H, s)

EXAMPLE 115

5-Bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(8-chloro-4-methoxybenzyl)-4-methoxybenzamide##STR188##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 67%).

M.P.: 223° to 229° C.

MASS: 555(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.50(4H, m), 1.90-2.02(4H, m), 2.18(1H, m), 2.26(1H, m), 3.83(3H,s), 3.87(3H, s), 4.39(2H, d, J=5.7 Hz), 7.11 (1H, d, J=8.4 Hz), 7.27(1H,dd, J=8.4, 2.2 Hz), 7.39(1H, d, J=2.2 Hz), 8.09(1H, s), 8.42(1H, s),9.24(1H, t, J=5.7 Hz), 11.92(1H, s), 12.01(1H, s)

EXAMPLE 116

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide##STR189##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 51%).

M.P.: 255° to 257° C.

MASS: 500(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.33-1.51(4H, m), 1.91-2.03(4H, m), 2.19(1H, m), 2.31(1H, m), 3.84(3H,s), 3.93(3H, s), 4.41(2H, d, J=5.5 Hz), 7.11(1H, d, J=8.4 Hz), 7.29(1H,dd, J=8.4, 2.2 Hz), 7.41(1H, d, J=2.2 Hz), 8.27(1H, s), 8.47(1H, s),9.28(1H, t, J=5.7 Hz), 12.01(1H, s), 12.19(1H, s)

EXAMPLE 117

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)-5-dimethylsulfamoylbenzamide##STR190##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 68%).

M.P.: 245° to 246° C.

MASS: 552(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.46(4H, m), 1.89-2.03(4H, m), 2.19(1H, m), 2.31(1H, m), 2.63(6H,s), 3.84(3H, s), 4.45(2H, d, J=5.7 Hz), 7.12(1H, d, J=8.4 Hz), 7.29(1H,dd, J=8.4, 2.0 Hz), 7.42(1H, d, J=2.0 Hz), 7.86(1H, dd, J=8.8, 2.2 Hz),8.10(1H, d, J=2.2 Hz), 8.64(1H, d, J=8.8 Hz), 9.58(1H, t, J=5.7 Hz),11.50(1H, s), 12.09(1H, s)

EXAMPLE 118

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)-5-methylsulfamoylbenzamide##STR191##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 38%).

M.P.: 247° to 249° C.

MASS: 538(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.31-1.48(4H, m), 1.88-2.03(4H, m), 2.18(1H, m), 2.30(1H, m), 2.41(3H,d, J:4.9 Hz), 3.84(3H, s), 4.45(2H, d, J=5.9 Hz), 7.12(1H, d, J=8.4 Hz),7.30(1H, dd, J=8.4, 2.2 Hz), 7.40(1H, q, J=4.9 Hz), 7.42(1H, d, J=2.2Hz), 7.86(1H, dd, J=8.8, 2.2 Hz), 8.10(1H, d, J=2.2 Hz), 8.55(1H, d,J=8.8 Hz), 9.53(1H, t, J=5.9 Hz), 11.30(1H, s), 12.08(1H, s)

EXAMPLE 119

2- (trans-4-Carboxycyclohexanecarbonyl)amino!-5-chloro-N-(2-methoxy-5-pyridyl)methyl!benzamide ##STR192##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 78%).

M.P.: 219° to 221° C.

MASS: 446(^(MH+))

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.48(4H, m), 1.85-2.02(4H, m), 2.13-2.29(2H, m), 3.83(3H, s),4.41(2H, d, J=5.7 Hz), 6.80(1H, d, J=8.6 Hz), 7.54(1H, dd, J=9.0, 2.4Hz), 7.70(1H, dd, J=8.6, 2.4 Hz), 7.81(1H, d, J=2.4 Hz), 8.16(1H, d,J=2.4 Hz), 8.38(1H, d, J=9.0 Hz), 9.33(1H, t, J=5.7 Hz), 11.13(1H, s),12.08(1H, s)

EXAMPLE 120

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-5-chloro-N-(3-cyano-4-methoxybenzyl)benzamide##STR193##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 77%).

M.P.: 190° to 193° C.

MASS: 470(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.46(4H, m), 1.84-2.02(4H, m), 2.12-2.28(2H, m), 3.90(3H, s),4.43(2H, d, J=5.7 Hz), 7.23(1H, d, J=8.8 Hz), 7.55(1H, dd, J=9.0, 2.6Hz), 7.65(1H, dd, J=8.8, 2.4 Hz), 7.70(1H, d, J=2.4 Hz), 7.78(1H, d,J=2.6 Hz), 8.36(1H, d, J=9.0 Hz), 9.34(1H, t, J:5.7 Hz), 11.10(1H, s),12.08(1H, s)

EXAMPLE 121

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-5-chloro-N-(4-chloro-3-methoxybenzyl)benzamide##STR194##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 38%).

M.P.: 224° to 225° C.

MASS: 479(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.29-1.46(4H, m), 1.85-2.01(4H, m), 2.13-2.28(2H, m), 3.86(3H, s),4.47(2H, d, J=5.9 Hz), 6.93(1H, dd, J=8.1, 1.5 Hz), 7.15(1H, d, J=1.5Hz), 7.37(1H, d, J=8.1 Hz), 7.56(1H, dd, J=9.0, 2.4 Hz), 7.85(1H, d,J=2.4 Hz), 8.39(1H, d, J=9.0 Hz), 9.39(1H, t, J=5.9 Hz), 11.16(1H, s),12.08(1H, s)

EXAMPLE 122

1- 4-Bromo-2-(3,4-methylenedioxybenzyl)carbamoyl!phenyl!carbamoyl!!carbamoyl!piperidine-4-carboxylicacid ##STR195##

The title compound was obtained as a white powder in a similar manner tothat of Example 110 (yield: 62%).

M.P.: 276° to 280° C. (dec.)

MASS: 504(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.47(2H, m), 1.86(2H, m), 2.49(1H, m), 2.98(1H, m), 3.91(2H, m),4.37(2H, d, J=5.7 Hz), 5.99(2H, s), 6.81(1H, dd, J=7.9, 1.6 Hz),6.87(1H, d, J=1.6 Hz), 6.92(1H, d, J=7.9 Hz), 7.61(1H, dd, J=9.2, 2.4Hz), 7.94(1H, d, J=2.4 Hz), 8.26(1H, d, J=9.2 Hz), 9.35(1H, t, J=5.7Hz), 11.07(1H, s), 12.30(1H, s)

EXAMPLE 123

4-Bromo-7-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)isoindoline-1-one##STR196##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 48%).

M.P.: 261° to 263° C.

MASS: 515(^(ME+))

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.34-1.54(4H, m), 1.95-2.06(4H, m), 2.21(1H, m), 2.37(1H, m), 4.29(2H,s), 4.63(2H, s), 6.00(2H, s), 6.83(1H, dd, J=7.9, 1.6 Hz), 6.89(1H, d,J=7.9 Hz), 6.91(1H, d, J=1.6 Hz), 7.71(1H, d, J=8.8 Hz), 8.28(1H, d,J=8.8 Hz), 10.38(1H, s), 12.01(1H, s)

EXAMPLE 124

5-Bromo-8-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-1,2,3,4-tetrahydroisoquinoline-1-one##STR197##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 45%).

M.P.: 241° to 244° C.

MASS: 529(^(MH+))

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.33-1.52(4H, m), 1.92-2.04(4H, m), 2.20(1H, m), 2.28(1H, m), 2.97(2H,t, J=8.1 Hz), 8.80(2H, t, J=6.8 Hz), 4.64(2H, s), 6.00(2H, s), 6.83(1H,dd, J=8.1, 1.5 Hz), 6.88(1H, d, J=8.1 Hz), 6.92(1H, d, J=1.5 Hz),7.73(1H, d, J=9.0 Hz), 8.45(1H, d, J=9.0 Hz), 12.10(1H, s), 12.39(1H, s)

EXAMPLE 125

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-trifluoromethoxybenzamide##STR198##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 72%).

M.P.: 245° to 250° C.

MASS: 509(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.31-1.48(4H, m), 1.88-2.03(4H, m), 2.14-2.32(2H, m), 4.39(2H, d, J=5.7Hz), 5.99(2H, s), 6.82(1H, dd, J=8.1, 1.6 Hz), 6.87(1H, d, J=8.1 Hz),6.94(1H, d, J=1.6 Hz), 7.52(1H, dd, J=9.2, 2.8 Hz), 7.76(1H, d, J=2.8Hz), 8.46(1H, d, J=9.2 Hz), 9.33(1H, t, J=5.7 Hz), 11.22(1H, s),12.09(1H, s)

EXAMPLE 126

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-(1-pyrazolyl)benzamide##STR199##

The title compound was obtained as a white needle similar manner to thatof Example 110 (yield: 65%).

M.P.: 219° to 221° C.

MASS: 491 (MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.49(4H, m), 1.89-2.03(4H, m), 2.15-2.31(2H, m), 4.42(2H, d, J=5.9Hz), 5.99(2H, s), 6.56(1H, dd, J=2.4, 1.8 Hz), 6.84(1H, dd, J=7.8, 1.5Hz), 6.87(1H, d, J=7.8 Hz), 6.95(1H, d, J=1.5 Hz), 7.76(1H, d, J=1.8Hz), 7.94(1H, dd, J=9.0, 2.6 Hz), 8.16(1H, d, J=2.6 Hz), 8.48(1H, d,J=9.0 Hz), 8.48(1H, d, J=2.4 Hz), 9.38(1H, t, J=5.9 Hz), 11.18(1H, s),12.08(1H, s)

EXAMPLE 127

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)-5-(1,2,4-triazol-1-yl)benzamide

2-(trans-4-Carboxycyclohexanecarbonyl)amino!-5-cyano-N-(3,4-methylenedioxybenzyl)benzamide##STR200##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 72%).

M.P.: 278° to 281° C. (dec.)

MASS: 492 (MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.50(4H, m), 1.90-2.03(4H, m), 2.15-2.33(2H, m), 4.43(2H, d, J=5.7Hz), 5.99(2H, s), 6.84(1H, dd, J=8.1, 1.1 Hz), 6.87(1H, d, J=8.1 Hz),6.95(1H, d, J=1.1 Hz), 7.96(1H, dd, J=9.0, 2.4 Hz), 8.21(1H, d, J=2.4Hz), 8.25(1H, s), 8.54(1H, d, J=9.0 Hz), 9.24(1H, s), 9.37(1H, t, J=5.7Hz), 11.23(1H, s), 12.09(1H, s)

EXAMPLE 128

5-Bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide##STR201##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 26%).

M.P.: 238° to 241° C. (dec.)

MASS: 450(MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.48(4H, m), 1.89-2.03(4H, m), 2.19(1H, m), 2.31(1H, m), 4.40(2H,d, J=5.7 Hz), 5.99(2H, s), 8.83(1H, dd, J=7.9, 1.5 Hz), 6.87(1H, d,J=7.9 Hz), 6.95(1H, d, J=1.5 Hz), 7.98(1H, dd, J=8.8, 2.0 Hz), 8.26(1H,d, J=2.0 Hz), 8.60(1H, d, J=8.8 Hz), 9.40(1H, t, J=5.7 Hz), 11.61(1H,s), 12.09(1H, s)

EXAMPLE 129

5-Bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-4-methoxy-N-(3,4-methylenedioxybenzyl)benzamide##STR202##

The title compound was obtained as a white needle in a similar manner tothat of Example 110 (yield: 26%).

M.P.: 245° to 249° C.

MASS: 533 (MH⁺)

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.32-1.50(4H, m), 1.90-2.18(1H, m), 2.26(1H, m), 3.87(3H, s), 4.37(2H,d, J=5.7 Hz), 5.99(2H, s), 6.80(1H, dd, J=7.9, 1.6 Hz), 6.86(1H, d,J=7.9 Hz), 6.91(1H, d, J=1.6 Hz), 8.10(1H, s), 8.42(1H, s), 9.21(1H, t,J=5.7 Hz), 11.96(1H, s), 12.01(1H, s)

EXAMPLE 130

5-Chloro-2-(2,5-dimethoxyphenylacetamido)-N-(3,4-methylenedioxybenzyl)benzamide##STR203##

The title compound was obtained as a whitecrystal in a similar manner tothat of Example 84 (yield: 55%).

MASS: 483(MH.sup.)

¹ H-NMR(400MHz, DMSO-d₆) δ:

3.60(2H, s), 3.68(3H, s), 3.71(3H, s), 4.32(2H, d, J=5.9 Hz), 6.00(2H,s), 6.77-6.94(6H, m), 7.53(1H, dd, J=8.6, 2.2 Hz), 9.26(1H, t, J=5.9Hz), 11.08(1H, s)

EXAMPLE 131

5-Chloro-2-(2,5-dimethoxybenzamido)-N-(3,4-methylenedioxybenzamide##STR204##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 56%).

MASS: 469(MH⁺)

¹ H-NMR(400 MHz, CDCl₃) δ:

3.84(3H, s), 4.04(3H, s), 4.52(2H, d, J=5.7 Hz), 5.94(2H, s), 6.34(1H,t, J=5.7 Hz), 6.73-6.84(3H, m), 6.95(1H, d, J=9.0 Hz), 7.06(1H, dd,J=3.1, 9.0 Hz), 7.38-7.44(2H, m), 7.77(1H, d, J=3.1 Hz), 11.71(1H, s)

EXAMPLE 132

4-Amino-5-bromo-2-(isonicotinoyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide ##STR205##

The title compound was obtained as a light-brown crystal in a similarmanner to that of Example 34 (yield: 78%).

¹ H-NMR(400 MHz, DMSO-d₆) δ:

4.38(2H, d, J=5.7 Hz), 5.98(2H, s), 6.19(2H, br s), 6.80(1H, dd, J=1.6,7.9 Hz), 6.86(H, d, J=7.9), 6.91(1H, d, J=1.6 Hz), 7.80(2H, d, J=5.9Hz), 8.05(1H, s), 8.22(1H, s), 8.84(2H, d, J=5.9 Hz), 9.10(1H, t, J=5.7Hz), 13.35(1H, s)

EXAMPLE 133

4-Amino-5-bromo-2-(4-tert-butylbenzenesulfonyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR206##

The title compound was obtained as a white powdery crystal in a similarmanner to that of Example 34 (yield: 79%).

M.P.: 234° to 235° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.25(9H, s), 4.28(2H, d, J=5.8 Hz), 6.00(2H, br s), 6.78(1H, dd J=1.6,8.1 Hz), 6.87(1H, d, J=1.6 Hz), 6.88(1H, d, J=8.1 Hz), 7.00(1H s),7.49-7.54(2H, m), 7.66-7.71(2H, m), 7.86(1H s), 8.97(1H, t, J=5.8 Hz),12.68(1H, s)

EXAMPLE 134

4-Amino-5-bromo-2-(methanesulfonyl)amino-N-(3,4-methylenedioxybenzyl)benzamide##STR207##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 41%).

M.P.: 178° to 180° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

3.08(3H, s), 3.83(3H, s), 4.33(2H, d, J=5.7 Hz), 6.17(2H, br s),6.94(1H, s), 7.11(1H, d, J=8.6 Hz), 7.25(1H, dd, J=2.0, 8.6 Hz),7.36(1H, d, J=2.0 Hz), 8.00(1H, s), 9.07(1H, t, J=5.7 Hz), 11.80(1H, s)

EXAMPLE 135

5-Bromo-2-(methanesulfonyl)amino-N-(3,4-methylenedioxybenzyl)benzamide##STR208##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 69%).

M.P.: 172° to 173° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

4.31(2H, d, J=5.9 Hz), 6.77(1H, dd, J=1.6 Hz, 7.9 Hz), 8.87(1H, d, J=1.6Hz), 6.89(1H, d, J=7.9 Hz), 7.45-7.55(3H, m), 7.60-7.74(4H, m), 9.33(1H,m), 11.58(1H, s)

EXAMPLE 136

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-((S)-5-oxo-2-tetrahydrofurancarbonyl)amino!benzamide ##STR209##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 24%).

¹ H-NMR(400 MHz, DMSO-d₆) δ:

2.23-2.35(1H, m), 2.52-2.63(3H, m), 3.84(3H, s), 4.43(2H, d, J=5.7 Hz),5.12-5.17(1H, m), 7.12(1H, d, J=8.6 Hz), 7.32(1H, dd, J=8.0, 2.4 Hz),7.43(1H, d, J=2.4 Hz), 8.00(1H, dd, J=1.6, 8.9 Hz), 8.30(1H, d, J=1.6Hz), 8.60(1H, d, J=8.9 Hz), 9.41(1H, t, J=5.7 Hz), 12.02(1H, s)

EXAMPLE 137

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-((R)-5-oxo-2-tetrahydrofurancarbonyl)amino!benzamide ##STR210##

The title compound was obtained as a white crystal in a similar mannerto hat of Example 34 (yield: 42%).

M.P.: 231° to 232° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

2.23-2.35(1H, m), 2.52-2.63(3H, m), 3.84(3H, s), 4.43(2H, d, J=5.7 Hz),5.12-5.17(1H, m), 7.12(1H, d, J=8.6 Hz), 7.32(1H, dd, J=8.0, 2.4 Hz),7.43(1H, d, J=2.4 Hz), 8.00(1H, dd, J=1.6, 8.9 Hz), 8.30(1H, d, J=1.6Hz), 8.60(1H, d, J=8.9 Hz), 9.41(1H, t, J=5.7 Hz), 12.02(1H, s)

EXAMPLE 138

4-Amino-5-bromo-2-trans-4-(ethoxycarbonyl)cyclohexanecarbonyl!amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR211##

The title compound as obtained as a white crystal in a similar manner tothat of Example 4 (yield: 59%).

¹ H-NMR(400 MHz, CDCl₃) δ:

1.26(3H, t, J=7.1 Hz), 1.44-1.64(4H, m), 2.06-2.14(4H, m), 2.25-2.36(2H,m), 4.13(2H, q, J=7.1 Hz), 4.42-4.49(4H, m), 5.97(2H, s), 6.30(1H, t,J=5.5 Hz), 5.97(2H, s), 6.83(1H, s), 7.49(1H, s), 8.20(1H, s), 11.57(1H,s)

EXAMPLE 139

4-Amino-5-bromo-N-(3-chloro-4-methoxybenzyl)-2-trans-4-(ethoxycarbonyl)cyclohexanecarbonyl!amino!benzamide ##STR212##

The title compound was obtained as a white crystal in a similar mannerto that of Example 84 (yield: 67%).

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.28(8H, t, J=7.1 Hz), 1.42-1.64(4H, m), 2.24-2.87(2H, m), 8.91(8H, s),4.13(2H, q, J=7.1 Hz), 4.46(2H, br s), 4.49(2H, d, J=5.6 Hz), 6.30(1H,t, J=5.6 Hz), 6.92(1H, d, J=8.4 Hz), 7.20(1H, dd, J=2.2, 8.4 Hz),7.87(1H, d, J=2.2 Hz), 7.49(1H, s), 8.21(1H, s), 11.54(1H, s)

EXAMPLE 140

4-Amino-5-bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(3,4-methylenedioxybenzyl)benzamide##STR213##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 75%).

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.47(4H, m), 1.90-1.99(4H, m), 2.13-2.24(2H, m), 4.33(2H, d, J=5.6Hz), 5.98(2H, s), 6.00(2H, br s), 6.77(1H, dd, J=1.6, 8.1 Hz), 6.88(1H,d, J=1.6 Hz), 7.90(1H, s), 8.04(1H, s), 8.95(1H, t, J=4.0 Hz), 11.93(1H,s)

EXAMPLE 141

4-Amino-5-bromo-2-(trans-4-carboxycyclohexanecarbonyl)amino!-N-(3-chloro-4-methoxybenzyl)benzamide##STR214##

The title compound was obtained as a white crystal in a similar mannerto that of Example 34 (yield: 64%).

M.P.: 274° to 276° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.30-1.47(4H, m), 1.90-1.98(4H, m), 2.12-2.23(2H, m), 3.83(3H, s),4.35(2H, d, J=5.6 Hz), 6.01(2H, br s), 7.11(1H, d, J=8.6 Hz), 7.25(1H,dd, J=8.6, 2.2 Hz), 7.36(1H, d, J=2.2 Hz), 7.90(1H, s), 8.03(1H, s),8.98(1H, t, J=5.4 Hz), 11.89(1H, s)

EXAMPLE 142

2-((R)-4-Carbamoyl-2-hydroxybutyryl)amino!-N-(3-chloro-4-methoxybenzyl)-5-cyanobenzamide##STR215##

N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-((R)-5-oxo-2-tetrahydrofurancarbonyl)amino!benzamide (500 mg) wasdissolved in 2.5 ml of 1,4-dioxane, followed by the addition of 2.5 mlof concentrated aqueous ammonia. The obtained mixture was heated underreflux for 2 hours and concentrated. The residue was purified by silicagel column chromatography (solvent: ethyl acetate) to give 150 mg of thetitle compound as a white crystal (yield: 29%).

M.P.: 168° to 170° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

1.68-1.80(1H, m), 1.95-2.05(1H, m), 2.12-2.30(2H, m), 3.84(3H, s),4.05-4.13(1H, m), 4.40-4.47(2H, m), 6.35(1H, br s), 6.79(1H br s),7.09-7.15(1H, m), 7.29-7.42(2H, m), 7.43(1H, d, J=2.0 Hz), 7.96(1H, dd,J=2.0, 8.8 Hz), 8.27(1H, d, J=2.0 Hz), 8.77(1H, d, J=8.8 Hz), 9.40(1H,t, J=5.7 Hz),

EXAMPLE 143

2,4-Diamino-N-(3,4-methylenedioxybenzyl)benzamide ##STR216##

4-Nitroanthranilic acid (7.0 g), piperonylamine (6.42 g),N,N'-dicyclohexylcarbodiimide (8.78 g), and 1-hydroxybenztriazole (5.75g) were added to 500 ml of acetonitrile. The obtained mixture was heatedat 60° C. for 3 hours, cooled and filtered to remove formed crystals.The filtrate was concentrated and extracted with ethyl acetate. Theethyl acetate phase was distilled to remove the solvent, giving crudecrystals. Ethanol (50 ml), N,N-dimethylformamide (50 ml) and platinumoxide (50 mg) were added to the formed crystals. The obtained mixturewas subjected to catalytic hydrogenation under an elevated pressure atroom temperature for 2 hours. The resulting reaction mixture was freedfrom the catalyst by filtration, and distilled to remove the solvent.Dichloromethane was added to the residue to conduct crystallization. Theformed crystals were recovered by filtration and dried to give 4.83 g ofthe title compound as a gray crystal (yield: 42%).

M.P.: 180° to 182° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

4.25(2H, d, J=8.0), 5.28(2H, s), 5.78-5.80(2H, m), 5.96(2H, s), 6.39(2H,s), 6.81-6.86(2H, m), 7.28(1H, d, J=9.2 Hz)., 8.21(1H, t, J=6.0 Hz)

EXAMPLE 144

5-Bromo-2,4-diamino-N-(3,4-methylenedioxybenzyl)benzamide ##STR217##

2,4-Diamino-N-(3,4-methylenedioxybenzyl)benzamide (6.47 g) was suspendedin 50 ml of ethanol, followed by the gradual addition of 3 ml of 47%aqueous hydrobromic acid. After the completion of the precipitation ofwhite crystals, the solvent was completely distilled off in a vacuum.Dimethyl sulfoxide (30 ml) was added to the residue and the obtainedmixture was heated at 150° C. under stirring for one hour and distilledin a vacuum to remove the dimethyl sulfoxide. The residue was purifiedby silica gel column chromatography (solvent: toluene/ethyl acetate (1:1)) to give 1.80 g of the title compound as a white crystal (yield:22%).

M.P.: 148° to 150° C.

¹ H-NMR(400 MHz, DMSO-d₆) δ:

4.25(2H, d, J=5.9 Hz), 5.45(2H, s), 5.97(2H, s), 8.02(1H, s), 8.49(2H,s), 8.74(1H, dd, J=1.8, 8.1 Hz), 8.82-8.88(2H, m), 7.82(1H, s), 8.44(1H,t, J=5.9 Hz),

We claim:
 1. An anthranilic acid derivative represented by the generalformula (I) or a pharmacologically acceptable salt thereof: ##STR218##wherein R¹, R², R³ and R⁴ represent the same or different from eachother, a hydrogen atom, a halogen atom, a hydroxy group, an optionallyhalogenated lower alkyl group, an optionally halogenated lower alkoxygroup, a nitro group, a hydroxyalkyl group, a cyano group, a group ofthe formula: ##STR219## wherein R⁹ and R¹⁰ represent the same ordifferent from each other, a hydrogen atom, an optionally halogenatedlower alkyl group, an arylalkyl group, a heteroarylalkyl group, an acylgroup or an optionally protected carboxyl group, or alternatively R⁹ andR¹⁰ together with the nitrogen atom to which they are bonded may form aring which may be substituted; and p is an integer of 0 to 6, anoptionally substituted tetrazolyl group, an optionally protectedcarboxyl group, an optionally substituted carbamoyl group, an optionallysubstituted pyrazolyl group, an optionally substituted imidazolyl group,a group of the formula: ##STR220## (wherein R¹³ represents a hydrogengroup or an optionally halogenated lower alkyl group; and q is aninteger of 0 to 2, or alternatively two substituents selected from amongR¹, R², R³ and R⁴ which are adjacent to each other may form a ringtogether with the carbon atoms to which they are bonded respectively;R⁵and R⁶ represent the same or different from each other, a hydrogen atom,a halogen atom, a hydroxy group, a cyano group, an optionallyhalogenated lower alkyl group or an optionally halogenated lower alkoxygroup, or alternatively R⁵ and R⁶ together with the carbon atoms towhich they are bonded respectively may form a cycloalkyl ring, anoxolane ring, a 1,3-dioxolane ring or a 1,4-dioxane ring; W represents agroup of the formula: --N= or --CH=; R⁷ and R⁸ represent the same ordifferent from each other, a hydrogen atom or an optionally halogenatedlower alkyl group, or alternatively R¹ and R⁷ together with the carbonatoms to which they are bonded respectively may form a ring which maycontain a nitrogen atom, an oxygen atom or a sulfur atom and which maybe substituted; A represents a hydrogen atom, an optionally halogenatedlower alkyl group or a group of the formula: --X--(CH₂)_(m) --Z whereinX represents --CO--, --CS--, --CH₂ -- or --S(O)₂ --; Z represents ahydroxy group, an optionally halogenated lower alkoxy group, a cyanogroup, a halogen atom, an optionally protected carbamoyl group, anoptionally substituted aryl group, an optionally substituted aryloxygroup, an optionally substituted heteroaryl group, an optionallysubstituted heteroarylalkyloxy group, a group of the formula: --NR¹¹ R¹²wherein R¹¹ and R¹² represent the same or different from each other, ahydrogen atom, an optionally halogenated lower alkyl group, anoptionally substituted arylalkyl group, an optionally substitutedheteroarylalkyl group, an acyl group, an optionally protected carboxygroup or an optionally substituted carbamoyl group, or alternatively R¹¹and R¹² together with the nitrogen atom to which they are bonded mayform a ring which may be substituted, or an optionally substitutedcycloalkyl group; and m is an integer of 0 to 6; Y represents an oxygenatom or a sulfur atom; and n is an integer of 0 to
 6. 2. An anthranilicacid derivative or pharmacologically acceptable salt thereof as setforth in claim 1, wherein Y is an oxygen atom.
 3. A preventive andtherapeutic agent for diseases wherein a phosphodiesterase inhibitoryaction is efficacious, which comprises an anthranilic acid derivative orpharmacologically acceptable salt thereof as set forth in claim 1 as anactive ingredient.
 4. A preventive and therapeutic agent for diseaseswherein a cyclic GMP phosphodiesterase inhibitory action is efficacious,which comprises an anthranilic acid derivative or pharmacologicallyacceptable salt thereof as set forth in claim 1 as an active ingredient.5. A preventive and therapeutic agent as set forth in claim 4, whereinsaid diseases include ischemic heart diseases, angina pectoris,hypertension, pulmonary hypertension, heart failure and asthma.
 6. Adrug composition comprising a pharmacologically effective amount of ananthranilic acid derivative or pharmacologically acceptable salt thereofas set forth in claim 1, and a pharmacologically acceptable carrier. 7.A method for the prevention and treatment of diseases, which comprisesadministering a pharmacologically effective amount of an anthranilicacid derivative or pharmacologically acceptable salt thereof as setforth in claim 1 to inhibit phosphodiesterase.